Le Infezioni in Medicina, n. 4, 469-479, 2022

doi: 10.53854/liim-3004-1

REVIEWS

Corticosteroids use for COVID-19: an overview of systematic reviews

Mario Cruciani, Ilaria Pati, Francesca Masiello, Simonetta Pupella, Vincenzo De Angelis

National Blood Centre, Italian National Institute of Health, Rome, Italy

Article received 9 September 2022, accepted 26 October 2022

Corresponding author

Mario Cruciani

E-mail: crucianimario@virgilio.it

SummaRY

Purpose: A reappraisal of the validity of the conclusions of systematic reviews (SRs) and meta-analyses related to corticosteroids use for the treatment of COVID-19.

Material and Methods: An overview of SRs (umbrella review). The methodological quality of the SRs was assessed using tha AMSTAR-2 checklist; quality of the evidence was appraised following the GRADE approach.

Results: 35 SRs were included in this overview. Data were from 307 overlapping reports, based on 121 individual primary studies (25 randomized clinical trials (RCTs), 96 non-RCTs. In critically ill patients the use of steroids significantly reduced mortality compared to standard of care in 80% of the SRs, more often with moderate/high level of certainty; however, in patients not requiring oxygen supplementation the use of steroids increased the overall mortality in 2/3 of the comparisons. Clinical progression of diseases (need for mechanical ventilation, or for intensive care admission) was more commonly observed among controls compared to steroids recipients (in 9 out of 14 comparisons; certainty of evidence from very-low to moderate). The occurrence of adverse events was similar among steroids recipients and controls. Other outcomes (i.e., viral clearance, length of hospital stay) or issue related to optimal dose and type of steroids were addressed in a minority of SRs, with a high level of uncertainty, so that no definitive conclusions can be drawn.

Conclusions: There is moderate certainty of evidence that corticosteroids reduce mortality and progression of disease in critically ill COVID-19 patients compared to standard of care, without increasing the occurrence of adverse events.

Keywords: Systematic review, meta-analysis, umbrella review, COVID-19, corticosteroids.

INTRODUCTION

The available evidence indicates that the rapid clinical progression of the diseases in patients with COVID-19 is directly related to the hyperinflammatory syndrome caused by a dysregulated host innate immune response [1]. Acute respiratory distress syndrome (ARDS) is one of the primary causes of death in patients with COVID-19 and is largely caused by elevated levels of pro-inflammatory cytokines (IL-6, IL-1, TNF-α, and interferon) referred to as cytokine storm [1, 2]. Not surprisingly, this has stimulated the development of anti-inflammatory therapies for the treatment of patients with COVID-19, and among them the use of IL- inhibitors and corticosteroids has been the object of numerous clinical studies, with inconsistent results [3-8]. Corticosteroids are used in several pulmonary disorders, including Severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS). While at the beginning of the SARS-CoV-2 pandemic the World Health Organization (WHO) counselled against use of corticosteroids in COVID-19 patients, after the publication of RECOVERY trial the WHO changed its initial advice and recommended the use of corticosteroids in patients with severe COVID-19 [4, 5, 9]. Given that, a considerable number of clinical trials have been conducted with the aim of evaluating the efficacy and safety of corticosteroids for COVID-19 patients, and others are in progress or in development. Due to the large amount of clinical data available, a number of systematic reviews (SRs) and meta-analysis have been published in the latest years. Nevertheless, their conclusions are quite inconsistent and reveal the extensive heterogeneity among studies in terms of design, conduct, and reporting. The current study is an overview of systematic reviews, also called umbrella review, and is aimed to reappraise the validity of the conclusions of the SRs and meta-analyses related to corticosteroids use for the treatment of COVID-19.

MATERIALS AND METHODS

This umbrella review is a part of a protocol registered on the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42021259625.

Review question/objective

The aim of this umbrella review is to evaluate the efficacy and safety of corticosteroids for the treatment of COVID-19 patients.

Inclusion and exclusion criteria

We considered for inclusion in this overview SRs that comprised randomized controlled trials (RCTs) and non-RCTs (i.e., prospective, retrospective, cross-sectional, cohort studies and case series) assessing the safety and efficacy of corticosteroids for the treatment of COVID-19 patients. Traditional reviews with no clear methodological approach were excluded from this umbrella review. SRs evaluating other viral infections were excluded unless they also reported data on SARS-CoV-2 infection that could be evaluated separately.

Clinical setting and participants

For this umbrella review, we considered SRs on COVID-19 at any stage of disease severity, from asymptomatic/pauci-symptomatic to life-threatening cases, and in any setting (outpatients and hospitalized patients).

Intervention and outcomes

Treatment with corticosteroids at any dose, timing and frequency was compared to standard of care (SOC) or placebo. We included the following outcomes: overall mortality, viral clearance, clinical progression, length of hospital stay, adverse reactions. Where available, we reported also results of subgroup analyses based on the severity of COVID-19 and on the design of the studies included in the SRs.

Search strategy

Relevant studies in four bibliographic databases (Embase, PubMed, Web of Science, and Cochrane library) were searched up to July 2022. The searches were carried-out without languages restriction using Medical Subjects Heading: (“COVID-19” OR “SARS-CoV-2”) AND (“systematic review” OR “meta-analysis”). Furthermore, we checked the reference lists of the most relevant manuscripts (original studies and reviews) to identify potentially eligible studies not captured by the electronic literature search.

Study selection and data extraction

All titles were screened by two independent assessors (MC and IP). Eligibility assessment was based on the title or abstract and on the full text if required. Full texts of possibly eligible articles were obtained and assessed independently by two reviewers (MC and IP). Both reviewers compared the articles identified. The two assessors also independently extracted quantitative and qualitative data from each selected study, with disagreements resolved through discussion and on the basis of the opinion of a third reviewer (FM). Findings are presented in tabular format with supporting text (Table 1). Quantitative tabulation of results includes: first author name and year of publication, the clinical condition under evaluation, principal characteristics of the study population, number of RCTs and non-RCTs included in the SR, intervention and control group, the outcomes assessed, and the main conclusion of the review as reported by authors.

Table 1 - Methodological quality of Systematic reviews assessed with the AMSTAR-2 tool.

Assessment of methodological quality of systematic reviews

We used the AMSTAR-2 critical appraisal checklist for SRs, a tool that evaluates both quantitative and qualitative reviews [10]. The tool is suitable for reviews including randomised and non-randomised studies. It includes 16 domains (7 considered critical) relating to the research question, review design, search strategy, study selection, data extraction, justification for excluded studies, description of included studies, risk of bias, sources of funding, meta-analysis, heterogeneity, publication bias, and conflicts of interest (see Table 2 for details of each question). Two review authors (MC, IP) independently assessed the quality of evidence in the included reviews and the methodological quality of the SRs. We resolved discrepancies through discussion or, if needed, through a third review author (FM). We did not exclude reviews based on AMSTAR 2 ratings, but considered the ratings in interpretation of our results.

Table 2 - Mortality data: comparisons based on the design of Systematic Reviews (SRs).

Summary of the evidence and appraisal of the quality of evidence

For the quantitative synthesis, we reported the effect size (odds ratio [OR], risk ratio [RR], risk difference [RD], Hazard ratio [HR] or risk difference [RD] with the 95% confidence intervals [CI]), as reported in individual reviews, and the main conclusions of each systematic review/meta-analysis The quality of evidence was appraised following the GRADE approach (Grades of Recommendation, Assessment, Development, and Evaluation). Whenever available, the grading of the quality of evidence reported in the included reviews was considered to define the quality of evidence. When grading of evidence was not reported by the authors of the study, the GRADE approach was applied in its five domains (risk of bias, indirectness, imprecision, inconsistency, and publication bias) basing on the information available from the study [11].

Furthermore, a three-color score was used for an immediate visual inspection of the comparison between intervention (steroids) and controls with regards to the main outcomes assessed: overall mortality, viral clearance, clinical progression, length of hospital stay, adverse events (green color: steroids confer advantage over standard therapy or placebo; red color: steroids do not confer advantage over standard therapy or placebo; yellow color: no clear advantage or disadvantage).

RESULTS

The electronic and manual search retrieved 4202 references The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram is reported in Figure 1. At the first stage of screening titles and abstracts, 45 references were selected. After the full texts were examined with regards to inclusion and exclusion criteria, 35 SRs were included in the umbrella review [12-46]. Ten SRs were excluded [47-56]. Reasons for exclusion were: SRs not covering or with no informative data on steroids therapy in COVID-19, protocol of a SR, case series [47-56].

Figure 1 - Flow chart of study selection process.

Description of the studies

Of the 35 SRs included in the overview, 29 were focused exclusively on COVID-19, while 6 focused also on other critical coronavirus infections (e.g., severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS) [12-15, 22, 40]. The 35 SRs included 307 overlapping reports (98 RCTs and 209 non-RCTs), based on 121 individual primary studies. The primary studies included 25 RCTs, 84 controlled non-RCTs, and 12 uncontrolled studies (single arm studies, including case series and case reports). Thirty-four SRs focused on systemic steroids as treatment of COVID-19, while one review [43] was focused on inhaled use of steroids. The main characteristics of the SRs included are summarized in Supplementary Table 1.

Supplemental Table 1 - Main characteristics of Systematic reviews included in the overview.

Methodological quality (Table 2)

Of the included reviews, two Cochrane reviews met all the AMSTAR-2 methodological requirements, and 4 (11.4%) had more than one unmet methodological requirements [15, 16, 18, 33, 38, 43]. Thirty-three reviews (94.2%) had 1 or more (from 1 to 8) methodological requirements partly met. Only 3 reviews (12.5%) report on the source of funding for the studies included in the review; 5 reviews (14.2%) did not mention that the methods of the review were registered in a protocol. Twelve reviews (34.2%) did not mention publication bias in material and methods and results, and failed to discuss the possible impact of publication bias on review findings. In one review participants, interventions, comparators, and outcomes (PICO) were not clearly made explicit, but in the remaining 34 reviews the design of the study was fully explained. In 8 reviews the search strategy was not comprehensive, mostly because the search did not include EMBASE. Study selection and screening was performed in duplicate by 88.5% of authors team (31/35). Other unmet or partly-met domains were related to the list of excluded reviews and reasons (1 and 5 reviews, respectively), assessment of risk of bias (4 and 4 reviews, respectively), and assessment of the potential impact of risk of bias in individual studies on the results of the meta-analysis or other evidence synthesis (4 and 2, respectively).

Summary of the effect of steroids on the main outcomes

Outcome “overall mortality”

Overall mortality was the most common reported outcome. Great heterogeneity was observed in several SRs; hence, when possible, we performed subgroup analyses to control for sources of heterogeneity such as severity of clinical conditions (e.g., according to the requirement of O2 supplementation, ICU admission, need of mechanical ventilation), design of studies included in the review (e.g., RCTs and non-RCTs), corticosteroids regimen used. The results of our analyses are summarized in Supplementary Table 2. Thirty-one SRs reported the outcome mortality, 14 including data only from RCTs [16, 21, 24-28, 30, 33, 34, 37, 41, 38], 5 from non-RCTs only 15, 17, 18, 22, 32], and the remaining 12 from both RCTs and non-RCTs [12-14, 19, 20, 23, 29, 31, 35, 36, 39, 40, 42-46]. A total of 48 comparison between steroids recipients and controls were performed in the included SRs, as summarized in supplemenrary Table 1 and supplementary table 2. The quality of the evidence according to the GRADE assessment was very-low in 13 comparisons, low in 19, moderate in 15, and high in one comparison. In 25 (52%) of these comparisons the effect size favoured the steroids arm compared to controls (level of evidence: high/moderate in 14 comparisons, low/very-low in 11), in five (10.4%) favoured the control arm (low or very-low level of evidence), while in 18 comparisons (37.5%) it was unclear if steroids reduced mortality compared to controls (level of evidence moderate in 2 comparisons, low or very-low in 16). As expected, the quality of the evidence was on average higher in SRs of RCTs only (Table 2). Moreover, compared to SRs including RCTs+non-RCTs and non-RCTs, SRs including RCTs only reported more commonly a reduction of mortality in steroids recipients than in controls (Table 2).

We also performed subgroup analysis of mortality according to severity of COVID-19, although this was limited by the heterogeneity in defining the clinical condition and inconsistency in reporting stratified data. In critically ill patients, including those requiring invasive mechanical ventilation and those with ARDS, the use of steroids therapy was found significantly more effective in reducing mortality compared to controls not receiving steroids in 80% (12/15) of the comparisons (low/very-low certainty of evidence in 5 comparisons, moderate/high in 7) [16, 19-24, 27, 31, 34, 37, 41], of unclear efficacy in 13% (2/15) of the comparisons (low and very-low certainty) [30, 36], and less effective than control in 1 comparison (very-low- certainty of evidence) [22]. By contrast, when the comparison included patients with different severity of infection (from severe to critical), the results were more heterogeneous, and the effect size favoured steroids use only in 12 out of 23 comparisons (52%); unclear results were reported in 10 comparisons (43%), and increased mortality in 1 comparison. However, in patients not requiring O2 supplementation the role of steroids compared to controls was detrimental in 4 out of 6 comparisons (66.6%; low certainty of evidence) [27, 29, 30, 41], and unclear in 2 comparisons [16, 37] (moderate and very-low certainty of evidence).

One SR [43] evaluated the use of inhaled steroids in asymptomatic SARS-CoV-2 infection or mild COVID-19, and concluded that it is unclear whether inhaled steroids + SOC reduces mortality compared to SOC alone (RR 0.61, 95% CIs 0.22/1.67; low level of certainty).

Outcome “Adverse events”

Adverse events were often not reported in the systematic reviews and, when reported, there was often inconsistency in describing type and severity of adverse events. In some of the systematic reviews there were just general statements about a similar occurrence of adverse events across groups of intervention. An effect size for serious adverse events and/or for any adverse events related to steroids was reported in 9 SRs for a total of 16 comparisons [15, 20, 21, 24, 26, 28, 30, 43, 44]; data were from 39 reports, based on 24 individual primary studies (11 RCTs and 13 non-RCTs). In 13 out of 16 comparisons (81%) the occurrence of adverse events (serious adverse events, any adverse events, gastrointestinal bleeding, secondary infections and hyperglycemia) were similar between steroids recipients and controls (Supplementary Table 2); the occurrence of adverse reactions was significantly higher in steroids recipients compared to control groups in 2 comparisons evaluating the occurrence of bacterial infection (very-low quality of certainty), and one evaluating the occurrence of hyperglycemia (moderate quality of evidence).

Supplemental Table 2 - Effects of corticosteroids on more commonly reported outcomes.

Outcome “clinical progression of disease”

Clinical progression of diseases was reported in 12 SRs (Supplementary Table 2), more commonly as need for mechanical ventilation (10 comparisons), or as need for ICU admission (2 comparisons), or as a clinical progression composite score (2 comparisons). Data were from 66 reports, based on 24 individual primary studies (7 RCTs and 17 non-RCTs). In 9 out of 14 comparisons (64.2%) the effect size favoured steroids compared to controls (from very-low to moderate certainty of evidence), in 3 it was unclear whether steroids decreased rate of clinical progression compared to controls (low certainty of evidence), while in one comparison based on 2 non-RCTs steroids increased rate of clinical progression compared to controls (very-low certainty of evidence).

Outcome “length of hospital stay”

Length of hospital stay was reported in 4 SRs, basing on 23 reports [17, 24, 29, 40]. Three SRs concluded that it is unclear if steroids decrease length of hospital stay compared to controls, while one shows a reduction of LOS in steroids recipients (Supplementary Table 2). The quality of evidence was graded as low.

Outcome viral clearance

The outcome viral clearance (rate of patients with negative reverse transcription polymerase chain reaction (RT-PCR) test for SARS-CoV-2 after a positive test at baseline) was reported in 5 SRs [17, 19, 20, 29, 44], basing on 29 reports (22 primary studies, including 1 RCT). In 3 SRs the viral clearance was not delayed in steroids recipients compared to controls (very-low certainty of evidence), but in 2 SRs [20, 29] the viral clearance in steroids recipients was delayed compared to controls (very-low certainty of evidence).

Steroids regimens

Data on the effect of pulse dose, high dose and/or low dose steroids were available from 5 SRs for the outcome mortality, from 4 SRs for the outcome progression of disease, from 2 SRs for the outcome length of hospital stay, and from one SR for the outcome adverse events (Supplemantary Table 2).

For the outcome mortality, low-dose steroids were found as effective as high-dose steroids in 2 comparisons from a SR (certainty of evidence from low to very-low) [39]. Low-dose steroids were found more effective than SOC in 2 SRs (certainty of evidence low and moderate) [30, 44], and as effective as SOC in one SR (VL certainty of evidence) [31]. High-dose steroids were found as effective as SOC in 2 SRs (low certainty of evidence) [31, 44].

For the outcome progression of disease (need for mechanical ventilation in 4 SRs, and admission to ICU in one), low-dose steroids were found as effective as high-dose steroids in 2 SRs [39, 42], and more effective than SOC in one SR [44] (from very-low to low certainty of evidence). High-dose steroids were found as effective as SOC in one SR (low certainty of evidence) [44].

Length of hospital stay was similar among patients receiving non-pulse dose or pulse-dose steroids [46], and in patients receiving high-dose or low-dose steroids (from low to very-low certainty of evidence) [39]. Likewise, no clear difference in the occurrence of hyperglicemia and secondary infections were found among low-dose and high-dose steroids recipients (moderate certainty of evidence) [39].

DISCUSSION

Umbrella reviews assemble together several systematic reviews on the same condition, and permit to consider for inclusion the highest level of evidence available, such as systematic reviews and meta-analyses [57, 58]. In this umbrella review we have reappraised the results of 35 SRs, published between 2020 and 2022, on the clinical use of steroids for COVID-19. The SRs included in this overview present data from 307 overlapping reports (98 RCTs and 209 non-RCTs), based on 121 individual primary studies (25 RCTs, 84 controlled non-RCTs, and 12 uncontrolled studies). We believe that makes this the largest review to date within this subject area, and hope this will make it particularly helpful to decision makers.

The main findings of this umbrella review are the following:

1) In critically ill patients (e.g., those requiring invasive mechanical ventilation and those with ARDS) the use of corticosteroids therapy was found significantly more effective in reducing mortality compared to SOC; this was demonstrated in 80% of the SRs (12/15) reporting this outcome, more often with moderate/high level of certainty (7/12).

2) When patients with different severity of infection were compared (from severe to critical), the results were more heterogeneous, and a decrease in mortality was reported in only 52% of the SRs.

3) In patients not requiring oxygen supplementation the use of steroids compared to controls increased the overall mortality in 4 out of 6 comparisons (66.6%).

4) Rate of clinical progression of diseases (more commonly defined as need for mechanical ventilation) was significantly higher in patients receiving SOC compared to steroids recipients, as demonstrated in 64.2% of the SRs reporting this outcome; the available evidence was graded from very-low to moderate.

5) In more than 80% of the SRs the occurrence of adverse events (serious adverse events, any adverse events, gastrointestinal bleeding, secondary infections and hyperglycemia) was similar among steroids recipients and controls; however, findings on the occurrence of adverse events can be biased because adverse events were often not reported in the systematic reviews and, when reported, there was often inconsistency in describing type and severity of adverse events.

Earliest published SRs/meta-analyses often included patients from observational studies, and also included data of coronavirus diseases caused by SARS-CoV-2, severe acute respiratory syndrome coronavirus, and Middle Eastern respiratory syndrome. Limitations to the methodological quality of reviews most commonly related to absence of publication bias assessment and funding sources of primary studies. Other limitations were rarely found, and usually were more commonly recorded in earliest published SRs, probably in relation to methodologic limitations of the primary studies available in that moment.

The clinical picture of COVID-19 has changed over time, both due to the emergence of viral variants and the spread of vaccinations. This obviously leads to additional difficulty in trial design and data analysis and interpretation. Overall, patients receiving corticosteroids with coronavirus diseases in the early phase of the epidemic were more likely to be critically ill; hence, there was a significant selection bias in non-RCTs included in the SRs. In this extremely uncertain and changing context, typical of emergency situations such as those of the COVID-19 pandemic, it is evident that also systematic reviews and meta-analyses have produced heterogeneous results [59, 60]. The results of RCTs are not always consistent with the results of observational studies, and differences in estimated magnitude of treatment effect are very common, often resulting in overestimation of treatment effects in observational studies [61]. Interpretation of the results obtained from both RCTs and observational studies, as well as from systematic reviews including both types of study design, can help understand the efficacy/effectiveness and safety of a therapeutic options [62]. For this reason, we performed, where possible, subgroup analyses of the effect size obtained in the overall comparison, in RCTs and in observational studies. For the outcome most commonly reported, overall mortality, it was possible to perform subgroup analysis of SRs according to study design and severity of COVID-19 at baseline. It was also clear that most of the included studies (both RCTs and non-RCTs) were at risk of bias and showed important clinical, methodological and statistical heterogeneity. Other outcomes (i.e., viral clearance, and length of hospital stay) were addressed by only a minority of SRs with a high level of uncertainty, so that no definitive conclusions can be drawn. Likewise, some of the SRs addressed the issue of the optimal dose (e.g., high and low-dose steroids) and type of steroids (e.g., dexamethasone, methylprednisolone, hydrocortisone) to be used for the treatment of COVID-19. In this respect the data available from primary studies and SRs are heterogeneous and sparse, so no firm conclusion can be drawn, but the interest in this area of research is timely and relevant, and several clinical trials evaluating the use of corticosteroids for the treatment of COVID-19 are underway or in development [63, 64].

Author contributions

Conceptualization: M.C and IP. Methodology: M.C. Data extraction: IP, FM, MC. Writing/preparation original draft: M.C. and IP. Writing/review and editing: IP, FM, SP, VDA. All authors have read and agreed to the published version of the manuscript.

Funding

No funding.

Conflicts of interest

The authors declare no conflict of interest in regard to this work.

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