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Corticosteroids

Last updated: April 30, 2021 

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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. However, several forms of corticosteroids have shown some degree of clinical benefit in COVID. 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.   

Corticosteroids have been studied via many routes of dosing, most recently the inhaled route, with a study of inhaled budesonide that has shown reduction in hospitalization among patients on inhaled budesonide.  

 

Guidelines  

IDSA guidelines recommend the use of corticosteroids in SARS-CoV-2 infection among hospitalized patients with severe COVID-19 (defined as patients with SpO≤94% on room air, or those who require either supplemental oxygen, mechanical ventilation or extracorporeal mechanical oxygenation) or those critically ill (defined as patients on mechanical ventilation and ECMO). Critical illness includes end organ dysfunction as is seen in sepsis/septic shock. In COVID-19, the most commonly reported form of end organ dysfunction is acute respiratory distress syndrome (ARDS). 

IDSA does not recommend the use of corticosteroids among hospitalized patients with non-severe COVID-19 (SpO2 >94%, not requiring supplemental oxygen). 

 

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.  
     
     

Key Literature 

In summary: To date, multiple randomized controlled trials have assessed the use of corticosteroids in hospitalized patients with COVID-19; overall, these studies suggest the use of dexamethasone and hydrocortisone reduce mortality in hospitalized patients with COVID-19 who require supplemental oxygen due to hypoxia (SpO2 ≤94% on room air). A number of observational studies have also been completed, and these have had mixed results; however, randomized controlled trial data is most reliable. Data is most supportive for dexamethasone.  

 

Comparison of efficacy of dexamethasone and methylprednisolone in moderate to severe COVID-19 disease (Fatima, December 2020). 

Overall, in this quasi-experimental study of 100 patients with COVID-19, there was an association of similar outcomes of dexamethasone and methylprednisolone in treating moderate to severe COVID-19 infection. 

Patient population: 

  • Quasi-experimental, interventional study of 100 COVID-19 patients in Pakistan. 
  • 35 patients received dexamethasone and 65 received methylprednisolone. 
  • Patients were also given tocilizumab and convalescent plasma as indicated. 
  • The mean age of patients was 57.91 years in the dexamethasone group and 54.86 years in the methylprednisolone group. 

Primary endpoint: 

  • To compare the efficacy and safety of dexamethasone versus methylprednisolone in moderate to severe COVID-19. 

Key findings 

  • In the dexamethasone group, 15 critically ill patients (42.8%) were shifted to the ICU and 7 of them (20%) needed ventilator support. 
  • In the methylprednisolone group, 22 patients (33.8%) were admitted to the ICU with 8 of them (12.3%) requiring ventilator support. 
  • Patients in both groups showed marked improvement in temperature, oxygen requirement and C-reactive protein on day 5. 
  • Six patients who received dexamethasone died (17.1%) versus 10 patients (15.3%) who received methylprednisolone. 

Limitations 

  • Small sample size and single-center study, which may limit generalizability of results. 
  • A higher percentage of patients in the dexamethasone group were critically ill and required ventilator support. 
  • Patients also received antibiotics, tocilizumab and convalescent plasma, which may have impacted results. 
  • Median time from start of corticosteroids upon admission to hospital was not stated. 

  

Corticosteroid therapy for coronavirus disease 2019-related acute respiratory distress syndrome: a cohort study with propensity score analysis (Wu, November 2020). 

Overall, in this single center retrospective study of 382 patients, low-dose corticosteroid treatment was associated with reduced risk of in-hospital death within 60 days in COVID-19 patients who developed acute respiratory distress syndrome. 

Patient population: 

  • Single-center retrospective observational study of 382 patients with acute respiratory distress syndrome caused by COVID-19 between Jan. 20 and Feb. 24, 2020. 
  • 226 patients (59.2%) received systemic corticosteroids and 156 (40.8%) received standard treatment.  
  • Among patients prescribed corticosteroids, methylprednisolone was the most frequently administered (213/226, 94.2%). 
  • The maximum dose of corticosteroids was 80.0 (IQR 40.0-80.0) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was 7.0 (4.0-12.0) days in total. 
  • Overall, the mean age ± SD was 60.7 years ± 14.1. 
  • The median was 2.0 (IQR 2.0-3.0). Of these cases, 94 (24.6%) patients had invasive mechanical ventilation. 
  • Corticosteroids were more likely to be prescribed to younger (p=0.0077) and male (p=0.0135) patients. 

Primary endpoint: 

  • To compare the risk of 60-day in-hospital mortality between COVID-19-related acute respiratory distress syndrome patients with corticosteroid treatment and those without. 

Key findings: 

  • The 60-day hospital death rate in patients who ever used corticosteroids was higher than the patients who did not use corticosteroids (135 [59.7%] vs. 68 [43.6%], p=0.0019). 
  • The median survival duration was longer in the corticosteroid group (19.0 [IQR 15.0–21.0] vs. 15.0 [IQR 12.0–23.0], p=0.0239). 
  • In Cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within 60 days after adjusting for age, sex, SOFA score at hospital admission, propensity score of corticosteroid treatment, comorbidities, antiviral treatment and respiratory supports (HR 0.42; 95% CI, 0.21, 0.85; p=0.0160). 
  • In the Cox regression model, there was no difference in time to viral shedding between the corticosteroids-treated group and the standard of care group (HR 1.43; 95% CI, 0.43, 4.80; p=0.5593). 

Limitations: 

  • This was not a randomized controlled trial; selection bias and the potential of confounding effects may exist. 
  • Only measured factors were controlled for due to the nature of observational study design. 
  • This study was single-center in design; therefore, there may be lack of generality. 

  

Corticosteroid treatment in severe COVID-19 patients with acute respiratory distress syndrome (Liu, November 2020). 

Overall, in this multicenter retrospective study, administration of corticosteroids, primarily methylprednisolone, in severe COVID-19-related acute respiratory distress syndrome was associated with increased 28-day mortality and delayed SARS-CoV-2 coronavirus RNA clearance after adjustment for time-varying confounders. 

Patient population: 

  • Retrospective multicenter study of 774 patients with COVID-19 and acute respiratory distress syndrome. 
  • 409 patients received corticosteroids, with a median time from hospitalization to starting corticosteroids of 1.0 day (IQR, 0.0–3.0 days); 365 patients received standard of care. 
  • Methylprednisolone was the most frequently used corticosteroid (396 of 409 [96.8%] patients) followed by prednisolone (32 of 409 [7.8%] patients). The maximum daily hydrocortisone-equivalent median dose of 200 mg (IQR, 200–400 mg) was used. The median duration of corticosteroid therapy was 6.0 days (IQR, 4.0–10.0 days). 
  • The median age was 64 years (IQR, 54–73 years) and 452 (58.0%) were male. 
  • 596 patients (77%) had one or more comorbidities. 
  • The median was 11 (IQR, 9–13). 

Primary endpoint: 

  • To explore the effects of corticosteroids on mortality from COVID-19 with acute respiratory distress syndrome and on the clearance of SARS-CoV-2 RNA compared to those receiving standard of care. 

Key findings: 

  • At 28 days, 181 of 409 (44.3%) patients in the corticosteroid group had died and 113 of 365 (31.0%) in the control group (OR, 1.77; 95% CI, 1.32–2.38; p<0.001). 
  • 185 out of 409 (45.2%) corticosteroid-treated patients died during hospitalization, compared with 115 of 365 (31.5%) controls (OR 1.79; 95% CI, 1.34–2.41; p<0.001). 
  • Multivariate logistic regression analysis suggested increased 28-day mortality with corticosteroids (adjusted OR 2.17; 95% CI, 1.36–3.53; p=0.001). 
  • After applying propensity score matching, 182 control and 182 case patients were matched. Corticosteroid therapy was significantly associated with increased 28-day mortality in multiple analyses, including Kaplan-Meier survival plot, multivariable logistic regression model (adjusted OR 1.64; 95% CI, 1.05–2.57; p=0.032) and extended multivariable Cox regression model, which treated corticosteroid use as a time-varying exposure variable (adjusted HR 1.46; 95% CI, 1.01–2.13; p=0.045). 
  • In subgroup analyses, high dose (>200 mg) and early initiation (≤3 days from hospitalization) of corticosteroid therapy were associated with a higher 28-day mortality rate. 
  • Corticosteroid therapy was associated with delayed SARS-CoV-2 RNA clearance among survivors by log-rank test (p=0.00017). 

Limitations: 

  • Retrospective design and some heterogeneity in the population, partly related to critically ill patients treated outside the ICU due to shortages in ICU beds. 
  • Some laboratory parameters (such as LDH, ferritin and CRP) were missing for some patients on admission, which may have introduced some biases. 
  • There was no long-term follow-up. 

  

Intravenous methylprednisolone pulse as a treatment for hospitalized severe COVID-19 patients: results from a randomized controlled clinical trial (Edalatifard, September 2020). 

Overall, in this small single-blind randomized study, patients with severe COVID-19 receiving methylprednisolone pulse had a significantly increased survival time, more clinical improvement and lower mortality compared to those receiving standard of care. 

Study population: 

  • A single-blind, randomized, controlled, clinical trial of 68 hospitalized patients with confirmed severe COVID-19 in Iran. 
  • Included patients were non-intubated adults, had confirmed COVID-19, SpO2 <90%, CRP >10, and IL-6 levels of >6. 
  • 34 patients were assigned to receive standard care and pulse-dose methylprednisolone (250 mg/day for 3 days) and 34 patients to standard care alone. 
  • The mean age of patients was 58.5±16.6 years old; 62.9% were men. 

Primary endpoint: 

  • Time of clinical improvement or death, whichever came first. 

Key findings: 

  • 22 patients (35.5%) had respiratory rate >24 breaths/min and 13 patients (21.0%) had heart rate >100 beats/min. 
  • The median interval time between disease symptom onset and hospitalization was 6.8±2.97 days. 
  • Patients with clinical improvement were higher in the methylprednisolone group compared to the standard care group (94.1% 57.1%), and the mortality rate was numerically lower in the methylprednisolone group (5.9% vs. 42.9%; p <0.001). 
  • Patients in the methylprednisolone intervention group had a significantly increased survival time compared with the patients in the standard care group (Log rank test: p<0.001; HR, 0.293; 95% C‎‎I, 0.‎154–0.556). 
  • 6 patients in the SOC group received corticosteroids from their prescribing physician and were excluded from the analysis. 

Limitations 

  • Single-blind design. 
  • 6 of the 34 patients (approximately 18%) in the SOC group were excluded from the analysis due to receiving corticosteroids; this could have altered the results, particularly given the small sample size. 
  • Lack of patient follow-up to identify long-term adverse events. 

  

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

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.  

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 (1,025 patients). 
  • Median age was 60 (IQR, 52-68), and 29% were female. 

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 1,025 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. 

Limitations: 

  • 2 of the 7 trials reported mortality at 21 and 30 days, respectively; this may have led 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. 

 

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).   

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.  

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.  

  

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

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

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 or 61.9% vs. 34/73 or 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.   

  

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).  

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.  

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%; RR, 0.64; 95% CI, 0.51-0.81), as well as those receiving oxygen without mechanical ventilation (23.3% vs. 26.2%; RR, 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%; RR, 1.19; 95% CI, 0.91-1.55).  

Limitations:  

  • The mortality rate of patients with severe COVID-19 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).   

 

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

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

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.  

  

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

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.  

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 OR, 0.41; 95% CI, .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.   

 

Additional Literature 

Inhaled Therapies 

As the SARS-CoV-2 virus enters the body through the respiratory route, the concentrations of antiviral in the airway epithelium can be considered most relevant for inhibiting initial viral replication in early infection. Delivering medications through a nebulized/inhaled route during early infection may avoid systemic toxicity. 

STOIC Trial: Inhaled budesonide in the treatment of early COVID-19 illness (Ramakrishnan, February 2021). This Phase II, randomized, controlled, open-label study assessed outcomes in non-hospitalized U.K. patients with mild COVID-19 who were randomized to receive either inhaled budesonide (800 µg dry powder inhaler twice daily) or placebo. Study participants were within 7 days of symptom onset, and those with recent use of systemic glucocorticoids were excluded. Endpoints included likelihood of requiring a COVID-19-related urgent care visit, emergency department care or hospitalization. Among 139 participants in the per-protocol analysis, the primary study outcome was reached in 1 of 70 participants in the budesonide arm and 10 of 69 participants in the standard of care arm (difference in proportion of 0.131, p=0.004; number needed to treat to prevent a single hospitalization was 8). Time to recovery was also reduced in the budesonide arm (median of 7 days versus 8 days in the usual care armlog rank test p=0.007), and participants in the budesonide arm were less likely to have symptoms at day 14 (10% vs 30% respectively, difference in proportions of 0.204, p=0.003). Of note, the study was not double blinded, and most participants were young and healthy, with low risk of progression to more severe disease; there was also no requirement that they have a positive SARS-CoV-2 test. (A sensitivity analysis among only participants with SARS-CoV-2 PCR-confirmed COVID showed a similar result: difference in proportions of 0.125, p=0.007.) The biological plausibility is twofold: 1) topical/inhaled steroids inhibit ACE-2 receptors, thus limiting viral entry; and 2) steroids may limit the airway inflammatory response to the virus. This is an encouraging proof-of-concept study among outpatients with mild COVID-19, and there is a need for larger-scale randomized controlled trials in multiple locales and with patients of older age and additional comorbidities.   

 

 

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 2020Siemieniuk, October 2015).  

 

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