Efficacy of Corticosteroids in Patients with SARS, MERS and COVID-19: A Systematic Review and Meta-Analysis

(1) Background: The use of corticosteroids in critical coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS), or Coronavirus disease 2019 (COVID-19), has been controversial. However, a meta-analysis on the efficacy of steroids in treating these coronavirus infections is lacking. (2) Purpose: We assessed a methodological criticism on the quality of previous published meta-analyses and the risk of misleading conclusions with important therapeutic consequences. We also examined the evidence of the efficacy of corticosteroids in reducing mortality in SARS, MERS and COVID-19. (3) Methods: PubMed, MEDLINE, Embase, and Web of Science were used to identify studies published until 25 April 2020, that reported associations between steroid use and mortality in treating SARS/MERS/COVID-19. Two investigators screened and extracted data independently. Searches were restricted to studies on humans, and articles that did not report the exact number of patients in each group or data on mortality were excluded. We calculated odds ratios (ORs) or hazard ratios (HRs) under the fixed- and random-effect model. (4) Results: Eight articles (4051 patients) were eligible for inclusion. Among these selected studies, 3416 patients were diagnosed with SARS, 360 patients with MERS, and 275 with COVID-19; 60.3% patients were administered steroids. The meta-analyses including all studies showed no differences overall in terms of mortality (OR 1.152, 95% CI 0.631–2.101 in the random effects model, p = 0.645). However, this conclusion might be biased, because, in some studies, the patients in the steroid group had more severe symptoms than those in the control group. In contrast, when the meta-analysis was performed restricting only to studies that used appropriate adjustment (e.g., time, disease severity), there was a significant difference between the two groups (HR 0.378, 95% CI 0.221–0.646 in the random effects model, p < 0.0001). Although there was no difference in mortality when steroids were used in severe cases, there was a difference among the group with more underlying diseases (OR 3.133, 95% CI 1.670–5.877, p < 0.001). (5) Conclusions: To our knowledge, this study is the first comprehensive systematic review and meta-analysis providing the most accurate evidence on the effect of steroids in coronavirus infections. If not contraindicated, and in the absence of side effects, the use of steroids should be considered in coronavirus infection including COVID-19.


PRISMA Checklist
. Checklist summarizing compliance with PRISMA guidelines [1]. Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

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Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

3-4
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

3-4
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

3-4 (Figure1)
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

3-4
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

3-4
Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

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Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Table 3, suppl 9-10

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Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

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Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

5-11, Supplementary tables
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

5-11
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

11-13
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

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Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
Title page 3

Reasons for study exclusion
We manually screened the retrieved articles which were met inclusion criteria. After excluding studies by examining titles and abstracts, full texts of 140 studies were eligible for inclusion. 132 studies were retrieved following reasons: Table S3. Reason for exclusion during full text screening.

Number of Studies Reason 81
Missing data on death or complication according to the use of steroids 28 Reviews or comments 11 Not accessible full paper even from the homepage of journal or authors 7 In vivo or in vitro studies 2 Not for outcomes of interest  10.Funding Sources Did the review authors report on the sources of funding for the studies included in the review? 1 1

11.Statistical Methods
If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? 0 1

12.RoB on metaanalysis
If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? -1

13.RoB in individual Studies
Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review? 0 1 6

14.Explanation for Heterogeneity
Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? 0 1

15.Publication Bias
If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? -1

16.Conflict of Interest
Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? 1 1 Total Score 2.5 16 Quality of assessment Low High

Study design
Study design was explained in the manuscript. All included studies had steroid group and non-steroid group (control) with the number of deaths as the primary outcome.

Statistical Methods
There was a statistical process combining raw data from all included studies.
Comprehensive meta-analyses were performed to combine study results to explain based on the statistical evidence. Heterogeneity and publication bias were also described.

Quality Assessment of the included Studies (Table S6-7)
We performed quality assessment of each included study based on an adapted version of Newcastle-Ottawa scale [11]. In each study, we divided the selection, the comparability, and outcome part to give scores for a total of 8 points. We ranked the studies according to the score (7 or more at high quality, moderate at 4 or more and less than 6, and Low quality 3 points or less. As a result, 2/9 (22.2%) of studies were high quality, 0/9 (0.0%) were moderate, and 7/9 (77.8%) were low quality. Bias was also assessed and higher scores indicate both higher study quality and lower risk of bias. Table S6. Quality assessment * of the cohort studies included in the meta-analysis (selection part).  2); C-Only described as 'corticosteroids' or 'steroids' without explaining about the kind and dose. † These are the same paper (Lau, 2009) [14] which has the two subgroups: one study in Hong-Kong(H) and the other study in Toronto (T). Table S7. Quality assessment * of the cohort studies included in the meta-analysis (Comparability/Outcome part).  (Information not provided). g A*-If prospective, all patients were evaluated for use of steroids during follow-up; B*-If prospective, <=10% of patients lost to follow up; C*-If retrospective, number of patients lost to follow-up or excluded is reported and <=10%; D-If retrospective or prospective, greater than 10% lost to follow up; E-If prospective or retrospective, number of patients lost to follow up not reported. h A*-Sufficient data and statistical test about steroids presented to support the primary outcome (mortality); B-The statistical test is not appropriate, not described or incomplete. † These are the same paper (Lau, 2009) [14] which has the two subgroups: one study in Hong-Kong (H) and the other study in Toronto (T). (Table S8-9)   Table S8. Detailed description about basal characteristics of included studies.      Studies are presented as country study (study [year]). The data are presented for total SARS studies about intervention (a), steroids as an add-on therapy for ribavirin (b), and steroids itself comparing non-steroid group (c). † These are the same paper (Lau (2009) [14]) which has the two subgroups: one study conducted in Hong-Kong (H1 and H2) and the other study in Toronto (T).