key: cord-1005067-9kx4al58
authors: Thakur, Manisha; Datusalia, Ashok Kumar; Kumar, Anoop
title: Use of steroids in COVID-19 patients: A meta-analysis
date: 2021-10-19
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2021.174579
sha: eae498f9074a8d51a007e10c749b33392211064e
doc_id: 1005067
cord_uid: 9kx4al58

BACKGROUND: Emerging reports have shown the benefits of steroids in hospitalized COVID-19 patients as life-saving drugs. However, the use of steroids in COVID-19 patients is confusing among many physicians. AIM: The aim of the current study was to find out the exact association of steroids in the deaths of COVID-19 patients. METHODS: The relevant studies were searched in PubMed, Google scholar, and Clinical trials registries till May 25, 2021 and sorted out based on inclusion and exclusion criteria. The quality of studies was assessed using a standard scale. The pooled odds ratio was calculated with a 95% confidence interval. The sensitivity and sub-group analyses were also done. The publication bias was assessed qualitatively. The Rev Man 5 was used for all analyses with a random-effect model. RESULTS: The quantitative analysis was done with 9922 patients (6265-male and 3657-females) from 21 relevant studies. The pooled estimate results i.e. 0.52 [0.34, 0.80] have shown a significant reduction in deaths of COVID-19 patients in the steroidal group as compared to the non-steroidal group. The sensitivity analyses did not alter our conclusions. In subgroup analysis, methylprednisolone has shown a significant reduction in deaths of COVID-19 patients as compared to the non-steroidal group, however, more clinical evidence is required for dexamethasone and hydrocortisone. CONCLUSION: The use of steroids in hospitalized COVID-19 patients is useful to reduce deaths.

The novel coronavirus (2019-nCoV) spreads from Wuhan City of China to the rest of the world (Singhal, 2020) . The first case was reported on 17 th November 2019 (Allam, 2020) . The Severe acute repiratory syndrome-Coronavirus-2 (SARS-Cov-2) is a positive single-strand ribose nucleic acid (RNA) virus having spike proteins on its surface which attach with the angiotensin-converting enzyme (ACE2) of the host and helps in the entry of the virus (Jha et al., 2021) . After entry, it uses the machinery of the host and results in the production of various viral proteins. The transmission of the infection occurs mainly through the inhalational route and symptoms appear between 2 to 14 days after the infection. The symptoms vary among the individuals and overlap with other viral infections. The reverse transcription polymaerase chain reaction (RT-PCR) is the most commonly used method for the detection of this infection. Other laboratory blood tests such as C-reactive protein (CRP) level, D-dimer, complete blood count (CBC) is also done to know about inflammatory and coagulation level of the individuals. It has been observed that patients with comorbid conditions like diabetes, obesity, hypertension, etc are more likely to get into serious conditions (Rahman et al., 2021; Yan et al., 2021) . Many researchers across the globe are working on the development of new chemical entities (NCEs) against this infection, however, no specific drugs are available in the market for its treatment so far (Singhal, 2020) . Various classes of drugs are repurposed for the management of COVID-19 cases including steroids, rapamycin, janus activated protein kinase (JAK) inhibitors (Patoulias et al., 2021) and antiandrogens (Franck, 2021; Fagone et al., 2020) .

Steroids are well-known drugs that are available in the market for the treatment of various diseases like rheumatoid arthritis, multiple sclerosis, crohn's disease, etc. Various case reports, case series, as well as research articles, have shown the benefits of using steroids in hospitalized COVID-19 J o u r n a l P r e -p r o o f patients (Van Paassen et al., 2020; Kalfaoglu et al., 2020; Chaudhuri et al., 2021) . Steroids are turned to be life-saving drugs for serious COVID-19 patients. The regulatory authorities also recommended the use of steroids in serious COVID-19 patients. On 2 nd September 2020, World Health Organization (WHO) has updated clinical care guidance and recommended the use of corticosteroids in severe and critical COVID-19 patients under medical supervision (WHO, 2020).

As per National Institute of Health (NIH) guidelines (updated on 3 rd November 2020), corticosteroids can be used in severe COVID-19 patients to control systematic inflammation (Fagone et al., 2020) . Recently, on 22 nd April 2021, Indian Council of Medical Research (ICMR) updated the guidelines and recommended the use of steroids like methylprednisolone in hospitalized COVID-19 patients if not contraindicated (ICMR, 2021) . It has been observed that the life of serious COVID-19 patients was saved using steroids but the exact role of steroids in COVID-19 patients is still an open question to answer. Thus, we have conducted a meta-analysis of available clinical evidence on the use of steroids in COVID-19 patients.

The study was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The study is registered with the International prospective register of systematic reviews Prospectively register of systematic reviews (PROSPERO), registration number CRD42021259891.

A search was done in PubMed, Google scholar, and Clinical trial registry for observational, randomized, and non-randomized controlled studies, cohort studies, and comparative crosssectional studies with the following search strategies. Steroids OR corticosteroids OR corticoids J o u r n a l P r e -p r o o f OR dexamethasone OR prednisone OR methyl prednisone OR prednisolone OR dexamethasone sodium phosphate OR hydrocortisone OR betamethasone OR beclomethasone OR budesonide OR formoterol AND COVID-19 OR SARS-CoV-2 OR severe acute respiratory syndrome OR Novel coronavirus. The references of included studies were screened to boost the search.

The inclusion criteria are as follows a) confirmed COVID-19 cases b) participants should be on steroidal therapy c) comparator group without steroidal therapy d) death should be one of the outcomes of study e) all age groups f) both male and female participants. Studies were excluded if -a.) study participants were not on steroidal therapy. b.) if there is no comparator group. c.) case reports, case series, narrative review, systematic review, meta-analysis d.) studies of poor quality as per standard scale. Two authors (MT and AK) separately screened all the titles and abstracts for eligibility criteria. Finally, the full-text articles were separately screened by two authors (MT and AK). In the case of conflicts over the inclusion, the third author (AKD) was consulted.

The quality assessment was done using Newcastle-Ottawa Scale (NOS). The assessment was done by two reviewers (MT and AK) separately. The studies were categorized into three categories i.e., good, fair, and poor quality.

The data was extracted from studies by two authors (MT and AK) in an excel sheet. The information such as name of the first author with publication year, name of the country where the study was conducted, study design, the total number of subjects, subjects in the steroid group, J o u r n a l P r e -p r o o f number of deaths in steroidal group, subjects in the non-steroidal group, number of deaths in the non-steroidal group was extracted from full-text articles.

The sensitivity analysis was done to check the effect of high or low sample size on the outcome.

All the analyses were performed using RevMan 5. The overall estimate was calculated as an odds ratio with 95% confidence intervals using a random effect model. The heterogeneity among studies was calculated using Cochrane Q and I square statistics. The publication bias was analyzed qualitatively using a funnel plot.

The 631 studies were found after the initial search. After removing duplicates and primarily screening of titles, 34 articles were retrieved, of which 21 articles (Villar et al., 2020; Salton et al., 2020; Petersen et al., 2020; Horby et al., 2021; Steroid SARI., 2020; Tomazini et al., 2020; Pontali et al., 2021; Rashad et al., 2021; Jamaati et al., 2021; Edalatifard et al., 2020; Ramiro et al., 2020; Tang et al., 2021; Corral-Gudino et al., 2021; Angus et al., 2020; Dequin et al., 2020; Liu et al., 2020; Ranjbar et al., 2021; Jeronimo et al., 2021; Fadel et al., 2020; Nelson et al., 2021; Ooi et al., 2020) were found to be appropriate for quantitative analysis as presented in figure 1 . The full-text or secondary screening with bibliography searching of the literature did not yield any additional article for inclusion. Out of the 21 studies, 13 studies were randomized control trials, 01 was retrospective, cohort, multi-centered quasi study each and the remaining 5 were clinical trials J o u r n a l P r e -p r o o f (CT). A total of 9,922 patients (male: 6265, female: 3657) were found. The study characteristics are compiled in table 1.

All randomized controlled trials (RCTs), clinical trials (CTs), cohort studies with one protocol assessed for methodological quality using Newcastle-Ottawa Scale (NOS) were found to be of good and fair quality, based on the scores of the study in the selection, comparability, and outcome subscales. Out of 21 studies, 15 were of good quality, and remaining 6 were of fair quality (table   2) .

A total of 21 studies contains 9,922 COVID-19 cases. Out of 9,922 COVID-19 cases, 4,018 were on steroids whereas 5,904 were in the non-steroid group. The overall estimate was 0.52 [0.34, 0.80] which indicates a significant decrease in deaths of COVID-19 patients in the steroidal group as compared to the non-steroidal group (figure 2). The funnel plot was not found to be symmetrical in shape which indicates involvement of publication bias (figure 3).

The sensitivity analysis was done to check the effect of outliers. In the current analysis, we have 5) . Finally, we have also excluded all the outliers with high and low sample sizes and found no effect on the conclusion of the study (figure 6).

The I 2 (90%) and chi 2 statics has shown high heterogeneity. However, after the removal of outliers, heterogeneity among studies was also reduced from 88% to 59%. 

Steroids are found to be life saving drugs in the management of COVID-19. It enters the cytoplasm and acts on the nuclear receptors which results in the synthesis of specific mRNA causes protein synthesis which lead to responses. It downregulating the hyper activation of the components of both innate (neutrophils) and acquired (T and B lymphocytes) immune system and the cytokine storm that characterizes severe case of covid-19 (Vanderbeke et al., 2021; Kalfaoglu et al., 2020; Sunkara and Dewan, 2021) .The current meta-analysis was performed to check the association of Cano et al (2021) meta-analysis results have also reported no effect (harmful or beneficial) between high and low-dose steroidal therapy. We have found a significant decrease in deaths of COVID-19 patients who are on steroids as compared to non-steroidal patients. The sensitivity analysis results also did not alter the findings of the study. The subgroup analysis results have shown a significant association of methyl-prednisolone in the reduction of deaths of COVID-19 patients, however, results with dexamethasone and hydrocortisone were found to be non-significant.

Overall, to get a clear picture of individual steroids, more evidence is required.

The study has the following limitations. The search for relevant articles has been performed on limited search engines. The articles which were published in the English language were only considered.

The steroids play a significant role in the decrease of demises of hospitalized COVID-19 patients.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors declare that they have no conflict of interest. 

Additional records identified through other sources (n = 08)

Records after duplicates removed (n = 34)

Records screened (n = 34)

Records excluded (n = 5)

Full-text articles assessed for eligibility (n =29)

Full-text articles excluded, with reasons n = 8, one article is related to meta-analysis and rest 7 are having insufficient information Studies included in qualitative synthesis (n = 21)

Studies included in quantitative synthesis (meta-analysis) (n = 21)

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

The First 50 days of COVID-19: A Detailed Chronological Timeline and Extensive Review of Literature Documenting the Pandemic. Surv. Covid-19 Pandemic its Implic

Writing Committee for the REMAP-CAP Investigators

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

Impact of Corticosteroids in Coronavirus Disease 2019 Outcomes: Systematic Review and Meta-analysis

Corticosteroids in COVID-19 and non-COVID-19 ARDS: a systematic review and meta-analysis

Methylprednisolone in adults hospitalized with COVID-19 pneumonia : An open-label randomized trial (GLUCOCOVID)

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial

Early Short-Course Corticosteroids in Hospitalized Patients With COVID-19

Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies

Do Anti-androgens Have Potential as Therapeutics for COVID-19?

Dexamethasone in Hospitalized Patients with Covid-19

Clinical guidance for management of COVID-19 patients

No clinical benefit of high dose corticosteroid administration in patients with COVID-19: A preliminary report of a randomized clinical trial

Current Understanding of Novel Coronavirus: Molecular Pathogenesis, Diagnosis, and Treatment Approaches. Immuno 2021

T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis

Corticosteroid treatment in severe COVID-19 patients with acute respiratory distress syndrome

Clinical Outcomes Associated With Methylprednisolone in Mechanically Ventilated Patients With COVID-19

Antivirals With Adjunctive Corticosteroids Prevent Clinical Progression of Early Coronavirus 2019 Pneumonia: A Retrospective Cohort Study

Corticosteroids for Patients With Coronavirus Disease 2019 (COVID-19) With Different Disease Severity: A Meta-Analysis of Randomized Clinical Trials

Janus kinase inhibitors and major COVID-19 outcomes: time to forget the two faces of Janus! A meta-analysis of randomized controlled trials

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan

Efficacy of early anti-inflammatory treatment with high doses of intravenous anakinra with or without glucocorticoids in patients with severe COVID-19 pneumonia

Corticosteroid therapy for COVID-19: A systematic review and meta-analysis of randomized controlled trials

Discovering common pathogenetic processes between COVID-19 and diabetes mellitus by differential gene expression pattern analysis

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study

Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial

Short term survival of critically ill COVID-19 Egyptian patients on assisted ventilation treated by either Dexamethasone or

Efficacy and safety of steroid therapy in COVID-19: A rapid systematic review and Meta-analysis

Glucocorticoid Therapy for COVID-19 Critically Ill Patients With Severe Acute Respiratory Failure

Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician's perspective

A Review of Coronavirus Disease-2019 (COVID-19)

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Coronavirus disease-2019: A review on the disease exacerbation via cytokine storm and concurrent management

2021. Early Use of Corticosteroid May Prolong SARS-CoV-2 Shedding in Non-Intensive Care Unit

Single-Blind

Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes

Lambrechts D, neutrophil activation as key mediators of COVID-19 disease severity

Efficacy of dexamethasone treatment for patients with the acute respiratory distress syndrome caused by COVID-19: Study protocol for a randomized controlled superiority trial

The proportion and effect of corticosteroid therapy in patients with COVID-19 infection: A systematic review and meta-analysis

Clinical management of severe acute respiratory infection ( SARI) when COVID-19 disease is suspected: interim guidance

The authors are thankful to Vice-Chancellor, Prof. R.K. Goyal, Delhi Pharmaceutical Sciences & Research University (DPSRU), New Delhi, and Director, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, India for their continuous support, motivation, and providing necessary facilities to carry out this work.