Corticosteroids In COVID-19 Management-A Systematic Review and Meta-Analysis Based on Recent Evidence

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has become a Public Health Emergency of International Concern (PHEIC) causing mortality due to cytokine storm syndrome and multiorgan failure. Corticosteroids have shown considerable efficacy in studies conducted on COVID-19 patients but the relative efficacy and safety for its compassionate use remain unclear. This meta-analysis aimed to evaluate available evidence on the efficacy of corticosteroids in the management of COVID-19 patients at various stages of the disease. In this meta-analysis, we included seven trials, and their pooled analysis revealed COVID-19 patients in the treatment group (n=3334) was lower as compared to the control group (n=5585). The overall pooled analysis among COVID-19 patients showed corticosteroids could decrease mortality (OR = 0.587, CI = 0.36-0.95, and p-value 0.029). Corticosteroids had an insignificant effect on viral clearance. Findings suggest that corticosteroids are helpful in managing COVID-19 patients although further research is required. Abbreviations: C-reactive


Background
Coronavirus disease-19 (COVID-19), a respiratory viral disease caused by SARS-COV-2, enveloped, and single-stranded coronavirus belongs to subgenus Sarbecovirus. The first case of COVID-19 turned up in Wuhan, a city of China. It spread rapidly and became the global epidemic affecting more than 213 countries across the globe [1]. According to the World Health Organization, the number of cases across the world reaches 23 million, and the number of death is 805,902 as of August 24, 2020 [2]. Some studies reported that most of the patient shows no symptoms at all or very mild symptoms and only 20 percent of patients develop respiratory problems and need hospitalization [3]. The morbidity of the patients is due to the progression of the respiratory infection to the hypoxemic respiratory failure and cytokines releasing syndrome, often requiring prolonged mechanical ventilation. The fatality rate reaches 26% in the United Kingdom and more than 37% in ventilation requiring patients [4]. According to available literature the corticosteroids were widely used in previous SARS pandemic in  in China and Hong Kong, and this leads to the usage of corticosteroid in COVID-19 in clinical trials [3,4]. Previously COVID-19 has been treated with drugs from various classes like antivirals, immune-modulating therapies, and anti-inflammatory drugs, and corticosteroid is an attractive option because of its potent anti-inflammatory mode of action and its previous regular usage in other respiratory conditions like severe acute respiratory distress syndrome. [5] But the use of systemic corticosteroid treating COVID DOI: 10.26717/BJSTR.2020.32.005280 25160 showed that patients treated without hydrocortisone show a low viral load in plasma and decreased viral shedding time than those treated with hydrocortisone [6].
According to some experts, corticosteroids increase viral shedding in lung damage and shock induced by a coronavirus and hence should not be used. [7] Various other trials showed promising results like recently in one of pre-published study, a randomized trial is conducted using a sample size of 11,303 patients in the different stage of COVID-19, show a reduction in 28 days mortality in the patients on oxygen therapy and mechanical ventilation using dexamethasone and their results lead to the global use of dexamethasone in COVID-19 patients [8]. Retrospective studies showed promising results of corticosteroid in SARS patients while in MERS patients, the usage of corticosteroids is not satisfactory, and patients require ventilation and renal replacement therapy. [9] In a nutshell, various trials and case studies showed a wide range of results. As the literature is rapidly expanding and continuously refilled every day, an updated meta-analysis featuring the latest literature is required. The aim of this systematic review and meta-analysis to assess the strength of evidence of usage of dexamethasone and other corticosteroids in the treatment of COVID-19. The study aims to obtain a single summary to quantify the results.

Search Strategies
In our study, we collected data by searching published articles in peer-reviewed journals by doing online search on article search engines like PubMed, Google Scholar, EMBASE, and Cochrane database from June 15th to July 31th, 2020. We searched articles by searching keywords "Coronavirus", "SARS-CoV-2", "Corticosteroids", "Dexamethasone", "treatment", and "effectiveness". We also searched these databases with individual drug names of corticosteroid family like, prednisolone, methylprednisolone, betamethasone, cortisone, and hydrocortisone. We also searched for the articles mentioned in the references of these articles.

Study Selection
We included randomized control trials and cohort studies investigating the effect of corticosteroid therapy among COVID-19 patients provided that: the medium of the reported article was English, the participants of the study were 18 years old or older, COVID-19 testing was done through RT-PCR, and analysis & outcome measures were given. We included the articles published in peer review journals from June 15 th to July 31 th 2020. The articles like editorials, perspectives, commentaries and short reviews were excluded.

Data Extractions
Two authors (SA and A) screened the rest of the articles independently. The articles on which two authors were of different views, whether to include them or not, the opinion of the third author (MASC) was obtained, and thus, the articles were screened out without any bias. The data we extracted and tabulated were the name of the articles, publication date, interventional drugs, number of participants, and any co-interventions used. Screening of the articles yielded a total number 14 articles following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, as shown in Figure 3.

Data Analysis
We conducted meta-analysis on the factors: effect of corticosteroid therapy on mortality, length of stay, ICU admission, adverse events, and risk of infection. Data analysis was conducted on RevMan 5.4. We analyzed pooled mean differences (MDs) and pooled adjusted Odds Ratios (OR), Hazard Ratios (HR), with 95% CIs , using the generic inverse-variance approach. The pooled analysis is shown graphically by forest plot. χ2 Cochran's Q test was employed to assess the statistical heterogeneity of studies. p value of 0.05 less was considered significant. For assessment and graphical representation of the heterogenicity and bias, we plotted the funnel plot using individual studies.

Search Results
Our database searches yielded 768 relevant articles. After were case series involving 8632 patients.

Study Characteristics
As 6 articles did not report relevant data on mortality, we reported outcomes on 7 studies (3334 patients receiving steroids and 5585 patients in the control group or not receiving steroids). The patient's mean age in the selected studies was

Viral Clearance
Among the 14 studies included in the metanalysis, 3 of them discussed the differential outcomes of corticosteroid therapy on viral clearance in treatment and control groups. showed that in both treatment and control groups, the difference in the viral clearance was insignificant (p = 0.252), which means that the time from onset of illness to viral clearance had no significant difference between two groups. studied the effect of methylprednisolone treatment on time taken for viral clearance. The results were insignificant in this trial (p = 0.713). Collectively, corticosteroids show no significant effect on viral clearance.

Length of Hospital Stay/ ICU days
Several studies investigated the effect of corticosteroid therapy on the length of hospital stay. [10,11] showed that the patients taking corticosteroids stayed admitted to the hospital for a longer time than the control group. The length of stay in the treatment group on average was 25 days, while the untreated group remained admitted on an average of, and these results are significant (p = 0.016). (Table 1) showed that the length of stay in the treatment group was less than that of the duration of hospital stay in the usual care group. Herrero et al. showed an insignificant relationship between a hospital stay and corticosteroid therapy (p = 0.091). in subgroup analysis, compared the timing of initial steroid dosing with ICU stay days when given less than 48 hours, mid between 48 hours and 7 days, and greater than 7 days after ICU. The association between use of corticosteroids and length of hospital stay was insignificant. to [12]., pulmonary embolism risk was significantly greater in the treatment group as compared to the control group (p = 0.0590).

Publication Bias
In order to check the publication bias, we plotted studies included in a literature on a funnel plot. Resultantly, no publication bias was founded ( Table 2).  13 Wang K, et al. [22] Critically ill Improved within 6 days and discharge on 17 days. A moderate dose of corticosteroid increased the chances of recovery of the critically ill patient 53 female History of hypertension 14 Kuzeva A, et l. [23] COVID-19 pneumonitis group was same. An increase hospital stay was observed in treated group as compared to control group [13]. Corticosteroid, as evident by a randomized trial study, decrease the "28-day mortality" [14] on invasive mechanical ventilation requirement. So, we can say Hence, it provides up-to-date and refined shreds of evidence.
In addition, all studies included in this meta-analysis provide [ [15][16][17] The optimal time for administration of steroids for better outcomes is the point of discussion in various reviews but none of the studies answered the mystery. But our results from included reports show that corticosteroid administration within 7 days after onset of illness is associated with better recovery, improved condition, and decrease ICU stay [18]. Methylprednisolone is the most commonly used steroid in the included studies.
And its administration on 1st, 2nd, 5th and 7th day from onset of illness show promising results. There are certain cointerventions along with corticosteroids including (tocilizumab, IV immunoglobulins and oseltamivir). The administration of corticosteroid with tocilizumab shows more promising results than corticosteroid alone. It reverse CT changes, decrease mortality but shows an increased risk of bacterial infection [10,17]. Coadministration of steroids with IV immunoglobulins in critical patients improves the severity of the disease, reverses cytokine syndrome, CT changes, and decreases mortality. Oseltamivir is administrated in a few patients as initial patient care prior to the administration of dexamethasone but no comment is given on its outcomes. [19] According to one negative study, that reports monotherapy with methylprednisolone having no effect on cure rate, death rate, clinical course, and adverse effects [14]. The studies included in this report have a variety of patients with different stages of COVID-19, so results concluded from these studies can be applied to any patient with any stage of disease not given by any other published systematic reviews and meta-analysis.
Almost every patient included in these studies has one of the  In conclusion, combination therapy of corticosteroids with tocilizumab or IV immunoglobulins are associated with surprisingly better outcomes, decreased rate of mortality, decreased in hospital stay, reversal of cytokine storm syndrome, and CT changes. Certain adverse effects are associated with them. Bacterial infection is the major risk. Interventions should be made to cope with them.
Because of the expanding knowledge and easy and over the counter availability of the steroids by healthcare systems, and the rapid spread of coronavirus across the globe, the area of corticosteroid research should be emphasized.

Conclusion
Recent evidence on the corticosteroids shows that the use of Corticosteroids therapy increases the risk of pulmonary embolism.
Recent evidence shows a weak link between corticosteroid therapy and admission in Intensive Care Unit (ICU).

Availability of Data and Materials
The datasets used and analysed during the current study are available from the corresponding author on reasonable request.