key: cord-0801855-udr22zf7
authors: Pasin, Laura; Navalesi, Paolo; Zangrillo, Alberto; Kuzovlev, Artem; Likhvantsev, Valery; Hajjar, Ludhmila Abrahão; Fresilli, Stefano; Lacerda, Marcus Vinicius Guimaraes; Landoni, Giovanni
title: Corticosteroids for COVID-19 patients with different disease severity: a meta-analysis of randomized clinical trials
date: 2020-11-28
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2020.11.057
sha: 83af249d1c8de3772c30d0426e25f7761ca093d3
doc_id: 801855
cord_uid: udr22zf7

OBJECTIVES: : Efficacy and safety of corticosteroids in patients with 2019-nCoV infection are still debated. Since large randomized clinical trials (RCTs) and a well conducted meta-analysis on the use of corticosteroids focused on COVID-19 intensive care unit patients were recently published, we performed a metanalysis of RCTs on corticosteroids therapy in patients with different disease severity to evaluate their effect on survival. DESIGN: : Meta-analyses of RCTs SETTING: : Hospital PARTICIPANTS: : COVID-19 patients INTERVENTIONS: : Corticosteroids MEASUREMENTS AND MAIN RESULTS: : We searched for RCTs performed on adult patients with acute hypoxemic failure related to 2019-nCoV infection, receiving corticosteroids versus any comparator. Primary endpoint was mortality rate. Five RCTs involving 7692 patients were included. Overall mortality of patients treated with corticosteroids was slightly but significantly lower than mortality of controls (26% vs 28%, RR=0.89 [95% CI 0.82 to 0.96], p=0.003). The same beneficial effect was found in the subgroup of patients requiring mechanical ventilation (RR=0.85 [95% CI 0.72-1.00], p=0.05 NNT=19). Remarkably, corticosteroids increased mortality in the subgroup of patients not requiring oxygen (17% vs 13%, RR=1.23 [95% CI 1.00 to 1.62], p=0.05 NNH=29). Tests for comparison between mechanical ventilated and not requiring oxygen subgroups confirmed that treatment with corticosteroids had a statistically significant different effect on survival. Patients treated with corticosteroids had a significantly lower risk of need for mechanical ventilation. CONCLUSIONS: : Corticosteroids may be weighed in severe critically ill COVID-19 patients, but must be discouraged in patients not requiring oxygen therapy. Further trials are urgently warranted before implementing this treatment worldwide.

Since the influenza outbreak of 1918, the COVID-19 pandemic probably represented the biggest global crisis faced by public health worldwide. Different drugs previously used to treat other coronavirus infections such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), were considered as the first potential candidates to treat COVID- 19 . Among them, in addition to other therapeutics, corticosteroids were widely used during SARS and MERS outbreaks and were recently adopted in patients with 2019-nCoV infection.

It is well known that acute respiratory distress syndrome is partly caused by host immune responses. 1 2019-nCoV virus, once entered into humans, targeting a key angiotensin-converting enzyme 2 (ACE2) receptor, replicates within cells causing cellular injury and/or death, with release of pro-inflammatory alarmins. 2 Moreover, viral particles can stimulate innate immune response, leading to the activation of alveolar macrophages and complement system. The resulted massive inflammatory response causes alveolar and vascular damage, microvascular thromboses and a progressive worsening of ventilation/perfusion mismatch. [3] [4] [5] In the late stages of the disease, the systemic inflammatory reaction may involve other organs causing multiorgan failure and death.

Theoretically, corticosteroid treatment could have a role to suppress lung inflammation, but also inhibit immune responses and pathogen clearance. Nonetheless, a recent meta-analysis on pharmacological agents for adults with acute respiratory distress syndrome found insufficient evidence to determine with certainty whether corticosteroids may reduce early all-cause mortality or the duration of mechanical ventilation. 6 Even less evidence exists in the literature to indicate whether corticosteroids are effective in treating coronavirus disease infection. 7 A recent large randomized clinical trial (RCT) showed that the use of dexamethasone resulted in lower 28-day mortality among COVID-19 patients who were receiving either invasive mechanical ventilation or oxygen alone at randomization, but not among patients receiving no respiratory support 8 . This study had immense resonance worldwide since, nowadays, dexamethasone is the first strategy proven to reduce mortality in COVID-19 patients. The updated living WHO guideline on drugs for covid-19 suggest not to use corticosteroids in the treatment of patients with non-severe covid-19 but with a weak or conditional recommendation. 9 Since other high-quality RCTs 10-13 and a well performed meta-analysis on the effect of corticosteroids focused on intensive care unit (ICU) patients were recently published 14 , we decided to perform a meta-analysis of RCTs on corticosteroids therapy to evaluate their effect on survival of subgroups of COVID-19 patients requiring different respiratory support.

Pertinent studies were independently searched in BioMedCentral, PubMed, Embase, medRxiv, bioRxiv and the Cochrane Central Register of clinical trials by two investigators (LP, GL). The full PubMed search strategy aimed to include any RCTs ever performed with corticosteroids in COVID-19 patients and is presented in the supplemental material. (Supplemental material) In addition, we employed backward snowballing (i.e., scanning of references of retrieved articles and pertinent reviews) and contacted international experts for further studies. No language restriction was imposed.

References were first independently examined at a title/abstract level by two investigators (LP, GL), with divergences resolved by consensus and then, if potentially pertinent, retrieved as complete articles. The following inclusion criteria were used for potentially relevant studies: random allocation to treatment (corticosteroids versus any comparator with no restrictions on dose or time of administration); studies involving patients with acute hypoxemic failure or pneumonia related to 2019-nCoV infection. The exclusion criteria were duplicate publications (in this case we referred to the first article published while retrieved data from the article with the longest follow-up available), non-adult patients and lack of data on all outcomes of interests. Two investigators (LP, GL)

independently assessed compliance to selection criteria and selected studies for the final analysis, with divergences resolved by consensus.

Baseline, procedural, and outcome data were independently abstracted by two investigators (LP; GL) ( Table 1) . At least two separate attempts at contacting original authors were made in cases of missing data. The primary endpoint of the present review was mortality rate at the longest available follow-up. Co-primary endpoints were mortality rate of mechanically ventilated patients and patients not receiving oxygen therapy. Secondary endpoint was need for mechanical ventilation.

The internal validity and risk of bias of included trials was appraised by two independent reviewers according to the latest version of the "Risk of bias assessment tool" developed by The Cochrane collaboration 15 , with divergences resolved by consensus. Publication bias was assessed by visually inspecting funnel plots.

Computations were performed with Review Manager version 5.4. Hypothesis of statistical heterogeneity was tested by means of Cochran Q test, with statistical significance set at the twotailed 0.10 level, whereas extent of statistical consistency was measured with I 2 , defined as 100% X (Q-df)/Q, where Q is Cochran's heterogeneity statistic and df the degrees of freedom.

Binary outcomes were analysed to compute the individual and pooled risk ratio (RR) with pertinent 95% confidence interval (CI), by means of the same models as just described. Binary outcomes from individual studies were analysed to compute individual and pooled risk ratio (RR) with pertinent 95% confidence interval (CI), by means of inverse variance method and with a fixedeffect model in case of low statistical inconsistency (I 2 25%) or with random-effect model (which better accommodates clinical and statistical variations) in case of moderate or high statistical inconsistency (I 2 >25%). Sensitivity analyses were performed by sequentially removing each study and reanalysing the remaining dataset (producing a new analysis for each study removed), by analysing only data from studies with low risk of bias and by analysing with a random effect analysis studies with low heterogeneity. Statistical significance was set at the two-tailed 0.05 level for hypothesis testing. Unadjusted p values were reported throughout. A pre-specified Trial Sequential Analysis (TSA) was performed on mortality outcome. We estimated the required information size on the calculated minimal intervention effect, considering a type I error of 5% and a power of 80%. This post hoc conservative approach allowed us to assess if the data were convincing enough to prove the effect.

To compare different groups (mechanical ventilated patients and patients not requiring oxygen therapy) with each other, we performed tests for subgroup differences based on random-effects models. In case of p values = 0.05 we repeated sensitivity analyses with Review Manager and Stata.

This study was registered on PROSPERO (CRD 42020197509) and performed in compliance with

The Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 16, 17 

Database searches, snowballing, and contacts with experts yielded a total of 1168 articles.

Excluding 1157 non-pertinent titles or abstracts, we retrieved in complete form and assessed 11 studies according to the selection criteria. (Figure 1 ) Six studies were further excluded because of our prespecified exclusion criteria: five because not randomized [18] [19] [20] [21] [22] and one because not reporting outcomes of randomized patients. 23 The five RCTs finally included in the meta-analysis involved 7692 patients (2835 received corticosteroids and 4837 received standard treatment). 8,10-13 ( Figure 2 ) No difference in mortality was found in the subgroups of patients who did not required intubation. ( Given the low number of included trials, funnel plots were not analysed.

Tests for comparison between mechanical ventilated and not requiring oxygen therapy subgroups based on random-effects models revealed that treatment with corticosteroids had a statistically significant different effect on survival in COVID-19 patients with different disease severity: χ2=7.55, P for effect=0.006; I 2 =86.7%. (Figure 2) 

This is the first meta-analysis of RCTs that shows that the effect of corticosteroids on patients' survival depends on the disease severity. In fact, while a recent meta-analyses published on JAMA by the REACT COVID group concluded that administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality in patients admitted to ICU, our study shows that the use of corticosteroids has detrimental effects on survival of patients not requiring oxygen with a number needed to harm = 29 and that a significant difference exists between the two patients cathegories. Unlike analyzing the whole ICU population as the REACT COVID group did, we focused our study on the different disease severity and achieved very informative results. This finding is of paramount importance since, fortunately, the majority of COVID-19 patients experience a mild or moderate illness and do not require hospital admission. Only a small minority of more severe patients are admitted to hospital where they often need oxygen therapy or respiratory mechanical support. Therefore, COVID-19 patients that might benefit from corticosteroids therapy are a tiny minority. In addition, we found that spontaneous breathing patients treated with corticosteroids had lesser requirement for intubation and mechanical ventilation, but higher mortality rate than patients who did not receive corticosteroids. These important findings, although apparently incongruous, stress the hypothesis that the use of corticosteroids might improve respiratory function (in patients who are already on oxygen), while probably increasing the risk of death (in patients who are not yet requiring oxygen).

The efficacy and safety of corticosteroids in COVID-19 is still debated. A recent large randomized clinical trial showed that the use of dexamethasone resulted in reduced 28-day mortality among patients who were receiving either invasive MV or oxygen alone, but not among patients who were receiving no respiratory support. 8 25 Similarly, corticosteroids have an overall beneficial effect in the majority of critically ill patients including those with pulmonary disease as suggested by a meta-analysis of RCTs. 26 We acknowledge that our study presents some limitations. Although it includes randomized clinical trials, the number of included studies is very low. Moreover, these trials do not reach the required sample size to verify the small difference in absolute mortality reduction we found between groups (2%). This small effect is probably already reduced since the currently observed in-hospital mortality appears to be rapidly reducing. 27 Nonetheless, since there were millions of COVID-19 cases throughout the World, even an absolute mortality reduction of 6% in mechanically ventilated patients (number needed to treat = 19) and an absolute mortality increase of 4% in patients not on oxygen (number needed to harm = 29) can save thousands of lives, especially of patients not requiring oxygen who are the vast majority of COVID-19 patients. In addition, initiation of oxygen therapy and/or mechanical ventilation, type of corticosteroid, dosage and duration of administration, concomitant antiviral/anti-inflammatory drugs were significantly different between studies.

Moreover, we included studies carried out both in ICU and ordinary ward, thus increasing overall heterogeneity. Nonetheless, the aim of our study was to investigate the effect of corticosteroids therapy on survival of subgroups of COVID-19 patients requiring different respiratory support.

Therefore, it was necessary to include patients admitted to different clinical setting since it is unlikely to find patients not requiring oxygen in the ICU. In addition, the role of confounding variables such as age, severity of disease, presence of pulmonary disease etc. remains to be explored.

In conclusion, our study clearly shows that the use of corticosteroids may be considered in severe critically ill COVID-19 patients, but must be discouraged in all patients not requiring oxygen support. Giver their small effect on survival of critically ill patients, they must be imperatively compared with other anti-inflammatory drugs since other therapies (eg anakinra) with better safety profile were recently tested with success. 28 Larger, high-quality randomized clinical trials on this topic are urgently warranted before implementing this treatment worldwide, in particular in the less critical, young patients not requiring oxygen therapy and/or hospitalization. 

Insights into the immunopathogenesis of acute respiratory distress syndrome

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis

Critically ill COVID-19 infected patients exhibit increased clot waveform analysis parameters consistent with hypercoagulability

COVID-19-related thromboinflammatory status: Microclots and beyond (editorial)

Pharmacological agents for adults with acute respiratory distress syndrome

Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease

Dexamethasone in Hospitalized Patients with

A living WHO guideline on drugs for covid-19

Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial

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

Writing Committee for the REMAP-CAP Investigators et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

RoB 2: A revised tool for assessing risk of bias in randomised trials

Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Handbook for Systematic Reviews of Interventions

The PRISMA statement for reporting systematic reviews and metaanalyses of studies that evaluate healthcare interventions: explanation and elaboration

IMPACT OF GLUCOCORTICOID TREATMENT IN SARS-COV-2 INFECTION MORTALITY: A RETROSPECTIVE CONTROLLED COHORT STUDY

Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19)

Systemic corticosteroids and mortality in severe and critical COVID-19 patients in Wuhan

Early Short Course Corticosteroids in Hospitalized Patients with COVID-19

TITLE: Beneficial Effect of Corticosteroids in Preventing Mortality in Patients Receiving Tocilizumab to Treat Severe

GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia

Antiviral agents, glucocorticoids, antibiotics, and intravenous immunoglobulin usage in 1142 patients with coronavirus disease 2019: a systematic review and meta-analysis

Mortality in COVID-19 patients with acute respiratory distress syndrome and corticosteroids use: a systematic review and meta-analysis

Steroids and Survival in Critically Ill Adult Patients: A Meta-analysis of 135 Randomized Trials

Decreased in-hospital mortality in patients with COVID-19 pneumonia

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.