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Corticosteroids

Last updated: August 24, 2020 

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview 

Dexamethasone, a corticosteroid, is the only drug found to have a mortality benefit in SARS-CoV-2 infection in a controlled trial. 

In some patients who progress to severe COVID-19 disease, it appears that the host immune response may lead to lung injury and multisystem organ dysfunction (Huang, January 2020Moore, May 2020). Multiple studies on the use of corticosteroids in severe COVID-19 are underway to determine how they may mitigate pathology resulting from hyper-inflammation.  

Guidelines 

IDSA guidelines recommend the use of corticosteroids in SARS-CoV-2 infection among hospitalized patients with severe COVID-19 disease (defined as patients with SpO2 ≤94% on room air, or those who require either supplemental oxygen, mechanical ventilation or extracorporeal mechanical oxygenation). 

IDSA does not recommend the use of corticosteroids among hospitalized patients with COVID-19 who do not have hypoxemia requiring supplemental oxygen. 

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Dosing

  • Dexamethasone 6 mg IV or PO for 10 days (or until discharge if earlier). 
  • Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg. 

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Key Literature  

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis (WHO REACT Group, Sept 2020)

Study population:

  • Meta-analysis of 7 randomized controlled trials from 12 countries, consisting of 1,703 critically ill patients with COVID-19.
  • Patients were randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or standard of care/placebo (1025 patients).
  • Median age was 60 (IQR 52-68), and 29% were women

Primary endpoint

  • To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.

Key findings

  • 7 trials were included; 6 trials were assessed as “low concern” for bias; 1 was assessed as “some concerns.”
  • The I2 was  15.6% (P = .31), indicating little heterogeneity between the trials
  • There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82) based on a fixed-effect meta-analysis)
  • The absolute mortality risk of 32% with corticosteroids compared with an assumed mortality risk of 40% with usual care or placebo. 
  • The association between administration of corticosteroids and reduced mortality was similar for dexamethasone and hydrocortisone
  • Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.

Limitation

  • 2 of the 7 trials reported mortality at 21 and 30 days, respectively; this may have lead to inconsistences in the results
  • Only adults were included in the trials, and most of them were conducted in high-income settings. This may limit the generalizability of the results
  • The majority of patients in the placebo/usual care arm were from the RECOVERY trial (59.1%), and overall RECOVERY contributed 57% to the weight in the analysis; this may have skewed the results

Overall, in this prospective meta-analysis of 7 randomized trials consisting of 1,703 patients, 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo. While a little over half of the weight of the study was due to the RECOVERY trial, findings were consistent across studies. This meta-analysis further supports the use of corticosteroids in critically ill patients with COVID-19 who require respiratory support.

 

Retrospective observational study examining corticosteroids within 48 hours of admission reduced mortality rates or the need for mechanical ventilation in hospitalized patients with COVID-19 (Keller, August 2020).  

Study population: 

  • 1,806 patients admitted with COVID-19 in a New York City health system. 

Primary endpoint: 

  • Mortality or need for mechanical ventilation.  

Key findings: 

  • 140 patients (7.7%) were treated with corticosteroids, while 1,666 (92.3%) never received corticosteroids.   
  • Corticosteroid use in patients with initial C-reactive protein (CRP) levels >20 mg/dL was correlated with significantly reduced risk of mortality or mechanical ventilation (OR, 0.23; 95% CI, 0.08-0.70). 
  • Corticosteroid use in patients with CRP levels <10 mg/dL was associated with significantly increased risk of mortality or mechanical ventilation (OR, 2.64; 95% CI, 1.39-5.03). 

Limitations: 

  • Retrospective, single-center observational design; therefore, confounding factors cannot be excluded. 
  • The type, dose and route of corticosteroid use is not reported. 

Overall, in this retrospective observational study, corticosteroid-treated patients with markedly elevated CRP benefited from corticosteroid treatment, while patients with lower CRP had higher mortality. 

 

Methylprednisolone as adjunctive for patients hospitalized with COVID-19 (Metcovid): a randomised, double-blind, Phase IIb, placebo-controlled trial (Jeronimo, August 2020). 

Study population: 

  • 416 hospitalized patients with confirmed or suspected COVID-19 disease at a single center in Brazil; infection was confirmed in 81.3% of patients. 
  • Patients received methylprednisolone (0.5 mg/kg twice daily for 5 days) or placebo. 
  • 393 patients were included in a modified intention-to-treat analysis.  

Primary endpoint: 

  • 28-day mortality. 

Key findings: 

  • 28-day mortality was 76/199 (38.2%) in the placebo group, versus 72/194 (37.1%) in the methylprednisolone group (p=0.629) 
  • Post-hoc analysis showed reduced mortality in the methylprednisolone group compared to the placebo group (52/84; 61.9% vs. 34/73; 46.65; p=0.039). 

Limitations: 

  • Single-center study. 
  • Authors used a modified intention-to-treat analysis; of 416 patients randomized, 393 were analyzed. While this could have affected the balance of the groups, authors note similar findings with an intention-to-treat analysis.  

Overall, in this randomized controlled trial, a short course of methylprednisolone in hospitalized patients with COVID-19 did not reduce mortality. 

 

RECOVERY trial: Controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with COVID-19 (The RECOVERY Collaborative Group, July 2020). 

Study population: 

  • 6,425 patients admitted with COVID-19 disease to 176 National Health Service hospitals in the U.K., of whom 2,104 were randomly allocated to receive dexamethasone (6 mg/day for up to 10 days) plus standard of care and 4,321 received standard of care alone. 

Primary endpoint: 

  • All-cause mortality within 28 days of randomization. 

Key findings: 

  • 482 patients (22.9%) in the dexamethasone arm and 1,110 patients (25.7%) in the standard of care group died within 28 days of randomization (p< 0.001).  
  • In the dexamethasone group, the incidence of death was lower than the standard of care arm among patients receiving mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51-0.81), as well as those receiving oxygen without mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72-0.94) 
  • In patients who were moderately ill but did not require oxygen at baseline, use of dexamethasone was associated with a non-statistically significant finding of increased mortality (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91-1.55). 

Limitations: 

  • The mortality rate of patients with severe COVID-19 disease found in this study is higher than what has been generally found in this group in the United States.  
  • Open-label design; researchers and patients in the study knew who was receiving which treatment. This could have introduced bias into the results. 
  • Not all patients had proven SARS-CoV-2 infection via RT-PCR.  
  • There was variability in how long patients received dexamethasone (the range was 3-10 days).  

Overall, in this controlled open label trial, dexamethasone reduced mortality in those patients receiving mechanical ventilation or oxygen. There was no benefit for patients who did not require respiratory support; in fact, there was a non-statistically significant trend toward increased mortality. 

 

Retrospective cohort study assessing risk factors for the development of acute respiratory distress syndrome (ARDS) and progression from ARDS to death (Wu, May 2020).  

Study population:  

  • 201 hospitalized patients with COVID-19 at a single center in Wuhan, China.  

Primary endpoint: 

  • Development of ARDS; death. 

Key findings: 

  • 84 patients (41.8%) developed ARDS, of whom 44 (52.4%) died. 
  • Among patients with ARDS, of those who received methylprednisolone treatment, 23 of 50 (46%) died, while of those who did not receive methylprednisolone, 21 of 34 (61.8%) died. 
  • In bivariate Cox regression analysis, among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).   

Limitations: 

  • Single-center retrospective study; therefore, the presence of confounding factors cannot be excluded. 
  • At the time only patients with severe disease were hospitalized. 
  • Only 10% of patients without ARDS were administered methylprednisolone; it is not disclosed if methylprednisolone was associated with lower death rate in the non-ARDS cohort.  
  • Symptom duration before methylprednisolone administration was not reported for any group.  

Overall, in this retrospective cohort study, among patients with ARDS, treatment with methylprednisolone was associated with significantly better outcomes. 

 

Single pretest, single posttest quasi-experiment of the use of corticosteroids for the treatment of moderate to severe COVID-19 disease (Fadel, May 2020). 

Study population: 

  • 213 patients with moderate to severe COVID-19 who received either standard of care, or standard of care and methylprednisolone 0.5 to 1 mg/kg/day divided in 2 intravenous doses for 3 days. 
  • Standard of care included antibiotic agents, antiviral agents or tocilizumab, as determined by the primary team. 

Primary endpoint: 

  • Composite endpoint of escalation of care from ward to intensive care unit, new requirement for mechanical ventilation and mortality. 

Key findings: 

  • 81 patients were included in the standard of care group and 132 in the early corticosteroid group.  
  • The composite endpoint happened at a lower rate in the early corticosteroid group (34.9% vs. 54.3%; p= 0.005).   
  • A significant reduction in median hospital length of stay was seen in the early corticosteroid group (8 vs. 5 days; p< 0.001). 
  • Multivariate regression analysis demonstrated an independent reduction in the composite endpoint at 14 days controlling for other factors (adjusted odds ratio: 0.41; 95% confidence interval, .22-.77). 

Limitations: 

  • Non-randomized design; confounding factors cannot be excluded. 
  • Many patients with moderate-severe disease received lopinavir-ritonavir, ribavirin and hydroxychloroquine. Tocilizumab may also have been given. This could have affected results 

Overall, in this non-randomized intervention study, an early short course of methylprednisolone in patients with moderate to severe COVID-19 reduced escalation of care and improved clinical outcomes. The results are limited by the use of other therapeutic agents.  

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Safety 

Patients receiving a short course of steroids may experience hyperglycemia, neurological side effects (e.g., agitation/confusion), adrenal suppression and risk of bacterial and fungal infection (Wu, March 2020,Siemieniuk, October 2015) 

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Resources 

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