Corticosteroids

Last Updated: November 3, 2020

Patients with severe COVID-19 can develop a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction. It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these deleterious effects. The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, a multicenter, randomized, open-label trial in hospitalized patients with COVID-19, showed that the mortality from COVID-19 was lower among patients who were randomized to receive dexamethasone than among those who received the standard of care.¹ Details of the RECOVERY trial are discussed in Clinical Data to Date, below.¹

The safety and efficacy of combination therapy of corticosteroids and an antiviral agent targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the treatment of COVID-19 have not been rigorously studied in clinical trials. However, there are theoretical reasons that such combination therapy may be beneficial in patients with severe disease. See Therapeutic Management of Patients with COVID-19 for the Panel’s recommendations on use of dexamethasone with or without remdesivir in certain hospitalized patients.

Rationale for Use of Corticosteroids in Patients With COVID-19

Both beneficial and deleterious clinical outcomes have been reported with use of corticosteroids (mostly prednisone or methylprednisolone) in patients with other pulmonary infections. In patients with Pneumocystis jirovecii pneumonia and hypoxia, prednisone therapy reduced the risk of death;² however, in outbreaks of other novel coronavirus infections (i.e., Middle East respiratory syndrome [MERS] and severe acute respiratory syndrome [SARS]), corticosteroid therapy was associated with delayed virus clearance.^3,4 In severe pneumonia caused by influenza viruses, corticosteroid therapy appears to result in worse clinical outcomes, including secondary bacterial infection and death.⁵

Corticosteroids have been studied in critically ill patients with acute respiratory distress syndrome (ARDS) with conflicting results.^6-8 Seven randomized controlled trials that included a total of 851 patients evaluated use of corticosteroids in patients with ARDS.^7-13 A meta-analysis of these trial results demonstrated that, compared with placebo, corticosteroid therapy reduced the risk of all-cause mortality (risk ratio 0.75; 95% CI, 0.59–0.95) and duration of mechanical ventilation (mean difference, -4.93 days; 95% CI, -7.81 to -2.06 days).^14,15

Recommendations on the use of corticosteroids for COVID-19 are largely based on data from the RECOVERY trial, a large, multicenter, randomized, open-label trial performed in the United Kingdom. This trial compared hospitalized patients who received up to 10 days of dexamethasone to those who received the standard of care. Mortality at 28 days was lower among patients who were randomized to receive dexamethasone than among those who received the standard of care.¹ This benefit was observed in patients who were mechanically ventilated or required supplemental oxygen at enrollment. No benefit of dexamethasone was seen in patients who did not require supplemental oxygen at enrollment. Details of the RECOVERY trial are discussed in Clinical Data to Date, below.¹

Corticosteroids used in various formulations and doses and for varying durations in patients with COVID-19 were also studied in several smaller randomized controlled trials.^16-20 Some of these trials were stopped early due to under enrollment following the release of the results from the RECOVERY trial. Given that the sample size of many these trials was insufficient to assess efficacy, evidence to support the use of methylprednisolone and hydrocortisone for the treatment of COVID-19 is not as robust as that demonstrated for dexamethasone in the RECOVERY trial.

Corticosteroids Other Than Dexamethasone

• If dexamethasone is not available, alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone can be used.
• For these drugs, the total daily dose equivalencies to dexamethasone 6 mg (oral or intravenous [IV])²¹ are:
  • Prednisone 40 mg
  • Methylprednisolone 32 mg
  • Hydrocortisone 160 mg
• Half-life, duration of action, and frequency of administration vary among corticosteroids.
  • Long-acting corticosteroid: dexamethasone; half-life: 36 to 72 hours, administer once daily.
  • Intermediate-acting corticosteroids: prednisone and methylprednisolone; half-life: 12 to 36 hours, administer once daily or in two divided doses daily.
  • Short-acting corticosteroid: hydrocortisone; half-life: 8 to 12 hours, administer in two to four divided doses daily.
• Hydrocortisone is commonly used to manage septic shock in patients with COVID-19; see Care of Critically Ill Patients With COVID-19 for more information. Unlike other corticosteroids previously studied in patients with ARDS, dexamethasone lacks mineralocorticoid activity and thus has minimal effect on sodium balance and fluid volume.¹⁰

Monitoring, Adverse Effects, and Drug-Drug Interactions

• Clinicians should closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, avascular necrosis).
• Prolonged use of systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus [HBV], herpesvirus infections, strongyloidiasis, tuberculosis).
• The risk of reactivation of latent infections for a 10-day course of dexamethasone (6 mg once daily) is not well-defined. When initiating dexamethasone, appropriate screening and treatment to reduce the risk of Strongyloides hyperinfection in patients at high risk of strongyloidiasis (e.g., patients from tropical, subtropical, or warm, temperate regions or those engaged in agricultural activities)^22-24 or fulminant reactivations of HBV²⁵ should be considered.
• Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer. As such, it may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates. Clinicians should review a patient’s medication regimen to assess potential interactions.
• Coadministration of remdesivir and dexamethasone has not been formally studied, but a clinically significant pharmacokinetic interaction is not predicted.
• Dexamethasone should be continued for up to 10 days or until hospital discharge, whichever comes first.

Considerations in Pregnancy

A short course of betamethasone and dexamethasone, which are known to cross the placenta, is routinely used to decrease neonatal complications of prematurity in women with threatened preterm delivery.^26,27

Given the potential benefit of decreased maternal mortality and the low risk of fetal adverse effects for a short course of dexamethasone therapy, the Panel recommends using dexamethasone in hospitalized pregnant women with COVID-19 who are mechanically ventilated (AIII) or who require supplemental oxygen but who are not mechanically ventilated (BIII).

Considerations in Children

The safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment have not been sufficiently evaluated in pediatric patients. Importantly, the RECOVERY trial did not include a significant number of pediatric patients, and mortality from COVID-19 is significantly lower among pediatric patients than among adult patients. Thus, caution is warranted when extrapolating the results of the RECOVERY trial to patients aged <18 years. Dexamethasone may be beneficial in pediatric patients with COVID-19 respiratory disease who require mechanical ventilation. Use of dexamethasone in patients who require other forms of supplemental oxygen support should be considered on a case-by-case basis and is generally not recommended for pediatric patients who require only low levels of oxygen support (i.e., nasal cannula only). Additional studies are needed to evaluate the use of steroids for the treatment of COVID-19 in pediatric patients, including for multisystem inflammatory syndrome in children (MIS-C).

Clinical Trials

Several clinical trials to evaluate corticosteroids for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.

Clinical Data to Date

Multicenter Randomized Controlled Trial of Dexamethasone Versus Standard of Care in Hospitalized Patients

Study Design

The RECOVERY study is an ongoing, multicenter, open-label, adaptive trial sponsored by the National Health Service in the United Kingdom. Eligible participants were randomized to receive one of several potential treatments for COVID-19 plus the standard of care or the standard of care alone. In one study arm, dexamethasone 6 mg daily was administered either orally or intravenously for up to 10 days or until hospital discharge, whichever came first. The primary study endpoint was all-cause mortality at 28 days after randomization. Secondary endpoints included time to hospital discharge, cause-specific mortality, need for renal replacement, major cardiac arrhythmia, and receipt and duration of ventilation. The results for the dexamethasone plus the standard of care versus the standard of care alone comparison are described below.¹

Study Population

Hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 infection were eligible for enrollment. Patients were not enrolled into the dexamethasone study arm (or included in the analysis) if their physicians determined that the risks of participation were too great based on their medical history or that corticosteroid therapy was indicated outside the study.

Preliminary Results

Participant characteristics

• The preliminary analysis included 6,425 participants: 2,104 participants in the dexamethasone plus standard of care arm and 4,321 in the standard of care alone arm.
• SARS-CoV-2 infection was confirmed by laboratory testing in 89% of the participants.
• The mean age of the participants was 66 years, 64% were men, 56% had at least one major comorbidity, and 24% had diabetes.
• At randomization, 16% of the participants received invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% required supplemental oxygen but not invasive ventilation, and 24% required no oxygen supplementation.
• Few participants received remdesivir, hydroxychloroquine, lopinavir/ritonavir, or tocilizumab (0% to 3% of the participants in both arms); approximately 8% of the participants in the standard of care alone arm received dexamethasone after randomization.

Study endpoint analyses

• Overall, 22.9% of participants in the dexamethasone arm and 25.7% in the standard of care arm died within 28 days of study randomization (age-adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P < 0.001).
• There was an interaction between baseline severity of COVID-19 and the treatment effect of dexamethasone.
  • Survival benefit appeared greatest among participants who required invasive mechanical ventilation at randomization: 29.3% of participants in the dexamethasone arm died within 28 days versus 41.4% in the standard of care arm (rate ratio 0.64; 95% CI, 0.51–0.81).
  • Among patients who required supplemental oxygen but not mechanical ventilation at enrollment, 23.3% of participants in the dexamethasone arm and 26.2% in the standard of care arm died within 28 days (rate ratio 0.82; 95% CI, 0.72–0.94).
  • No survival benefit was seen among participants who did not require oxygen therapy at enrollment; 17.8% of participants in the dexamethasone arm and 14.0% in the standard of care arm died within 28 days (rate ratio 1.19; 95% CI, 0.91–1.55).
• The risk of progression to invasive mechanical ventilation was lower in the dexamethasone arm than in the standard of care arm (rate ratio 0.77; 95% CI, 0.62–0.95).

Limitations

• The study was randomized, but open label.
• In this preliminary report, the results for key secondary endpoints (e.g., cause-specific mortality, need for renal replacement), potential adverse events, and efficacy of dexamethasone in key subgroups (e.g., patients with comorbidities) have not been reported.
• Study participants with COVID-19 who required oxygen but not mechanical ventilation had variable disease severity; it is unclear whether all patients in this heterogeneous group derived benefit from dexamethasone, or whether benefit is restricted to those requiring higher levels of supplemental oxygen or oxygen delivered through a high-flow device.
• The age distribution of participants differed by respiratory status at randomization.
  • The survival benefit of dexamethasone for mechanically ventilated patients aged >80 years is unknown, because only 1% of this group was ventilated.
  • It is unclear if younger patients were more likely to receive mechanical ventilation than patients aged >80 years, given similar disease severity at baseline, with older patients preferentially assigned to oxygen therapy. If so, then the disease severity would vary by age within the oxygen group, contributing to the difficulty in interpreting the observed mortality benefit in this heterogeneous group.
• Very few pediatric or pregnant patients with COVID-19 were included in the RECOVERY trial; therefore, the safety and efficacy of dexamethasone for the treatment of COVID-19 in children or in pregnant individuals are unknown.

Interpretation

In patients with severe COVID-19 who required oxygen support, using dexamethasone 6 mg daily for up to 10 days reduced mortality at 28 days. The benefit of dexamethasone was most apparent in hospitalized patients who were mechanically ventilated. There was no observed benefit of dexamethasone in patients who did not require oxygen support.

Meta-Analysis of Corticosteroids for Critically Ill Patients With COVID-19

Study Design

This meta-analysis performed by the World Health Organization (WHO) included pooled data from seven randomized clinical trials of corticosteroids in critically ill patients with COVID-19.²⁰

Patient Population

• The analysis included 1,703 critically ill patients with COVID-19 who were participants in trials conducted in 12 countries from February 26 to June 9, 2020.
• Across the studies, 678 patients received corticosteroids (i.e., dexamethasone, hydrocortisone, methylprednisolone), and 1,025 received usual care or placebo.
• Overall, 1,559 of the patients (91.5%) were on mechanical ventilation.
• The median age of the patients was 60 years (IQR 52–68 years); 488 (28.7%) were women.
• Across the six trials that provided data on the use of vasoactive agents, 47.0% of the patients were on the agents at randomization.
• Mortality was assessed at 28 days (five trials), 21 days (one trial), and 30 days (one trial).

Results

Key primary and secondary outcomes

• The reported mortality was 32.7% (222 of 678 patients) in the corticosteroids group and 41.5% (425 of 1,025 patients) in the usual care or placebo group (summary OR 0.66 [95% CI, 0.53-0.82; P < 0.001] based on a fixed-effect meta-analysis).
• The fixed-effect summary ORs for the association with all-cause mortality were:
  • Dexamethasone: OR 0.64 (95% CI, 0.50–0.82; P < 0.001) in three trials with 1,282 patients
  • Hydrocortisone: OR 0.69 (95% CI, 0.43–1.12; P = 0.13) in three trials with 374 patients
  • Methylprednisolone: OR 0.91 (95% CI, 0.29–2.87; P = 0.87) in one trial with 47 patients
  • For patients on mechanical ventilation (n = 1,559): OR 0.69 (95% CI, 0.55–0.86) corresponding to an absolute risk of 30% for corticosteroids versus 38% for usual care or placebo
  • For patients not on mechanical ventilation (n = 144): OR 0.41 (95% CI, 0.19–0.88) corresponding to an absolute risk of 23% for corticosteroids versus 42% for usual care or placebo
  • For the association between corticosteroids and mortality among patients who were receiving vasoactive agents at randomization: OR 1.05 (95% CI, 0.65–1.69) (an absolute risk of 48% for corticosteroids vs. 47% for usual care or placebo)
  • For the association between corticosteroids and mortality among patients who were not receiving vasoactive agents at randomization: OR 0.55 (95% CI, 0.34–0.88) (an absolute risk of 24% for corticosteroids vs. 37% for usual care or placebo)

Safety

• Serious adverse events were reported in six of the seven trials. Serious adverse events occurred in 18.1% of the patients randomized to corticosteroids (64 of 354 patients) and in 23.4% of the patients randomized to usual care or placebo (80 of 342 patients).

Limitations

• The design of the trials included in the meta-analysis differed in several ways, including the following:
  • Definition of critical illness, which ranged from requirement for oxygen supplementation >10 L/minute to requirement for intubation with moderate to severe acute ARDS
  • Specific corticosteroid used
  • Dose of corticosteroid: high dose in three trials (322 patients), low dose in four trials (1,381 patients)
  • Control group: usual care in five trials, placebo in two trials
  • Duration of corticosteroid treatment
  • Reporting of serious adverse events
• The RECOVERY trial accounted for 59.1% of the participants (1,007) in this meta-analysis, and participants from the other six trials accounted for 40.9% of the total population (696 participants). Three trials enrolled fewer than 50 patients.
• Some of the trials closed early after the results from the RECOVERY trial were reported.
• Some studies required that participants had confirmed SARS-CoV-2 infection; others enrolled participants with either probable or confirmed infection. Confirmed cases ranged from 79% to 100% across the trials.
• Although the risk of bias was low in six of the seven trials, it was assessed as “some concerns” for one trial. This trial contributed only 47 patients to the analysis.

Interpretation

Systemic corticosteroids decrease 28-day mortality in patients with COVID-19 without safety concerns, based on the meta-analysis of the seven randomized controlled trials. Because most of the participants (59%) in this meta-analysis were from the RECOVERY trial, it is likely that the benefits observed were mostly associated with dexamethasone, the corticosteroid used in the RECOVERY trial.

Single-Center Randomized Controlled Trial of Methylprednisolone Versus Placebo in Hospitalized Patients in Brazil

Study Design

Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid) is a randomized, double-blind, placebo-controlled, single-center study in Brazil that evaluated the use of short-course methylprednisolone (0.5 mg/kg twice daily for 5 days) versus placebo in hospitalized patients with confirmed or suspected COVID-19 pneumonia.¹⁶

Results

Participant characteristics

• A total of 416 participants were randomized; 393 were included in the modified intention-to-treat (mITT) analysis (194 from the methylprednisolone arm and 199 from the placebo arm).
• SARS-CoV-2 infection was confirmed in 83% and 79% of the participants who received methylprednisolone and placebo, respectively.
• The mean age of the participants was 55 years; 65% were men and 29% had diabetes.
• At enrollment, 34% of the participants in each group required invasive mechanical ventilation, and 51% of the participants in the methylprednisolone group and 45% in the placebo group required supplemental oxygen.
• The median time from illness onset to randomization was 13 days (IQR 9–16) in both groups.
• Among the participants who required mechanical ventilation at study entry, the median time from mechanical ventilation to randomization was 4 days in the methylprednisolone arm and 3 days in the placebo arm.
• None of the participants received anti-interleukin (IL)-6, anti-IL-1, remdesivir, or convalescent plasma.
• Hydrocortisone use (per clinician discretion) in patients with shock was reported in 8.7% and 7.0% of the participants in the methylprednisolone and placebo groups, respectively.

Study endpoints

• Primary outcome: There was no difference between the arms in 28-day mortality: 37.1% of the participants in the methylprednisolone arm and 38.2% in the placebo arm died by Day 28 (HR 0.92; 95% CI, 0.67–1.28; P = 0.629).
• Secondary outcomes: There was no difference between the arms in early mortality at Days 7 and 14 or in the need for mechanical ventilation by Day 7.
  • Mortality at Day 7: 16.5% and 23.6% of participants in the methylprednisolone and placebo arms, respectively (HR 0.68; 95% CI, 0.43–1.06; P = 0.089)
  • Mortality at Day 14: 27.3% and 31.7% of participants in the methylprednisolone and placebo arms, respectively (HR 0.82; 95% CI, 0.57–1.18; P = 0.29)
  • Need for mechanical ventilation by Day 7: 19.4% and 16.8% of participants in the methylprednisolone and placebo arms, respectively (P = 0.65)
• Post-hoc analysis: The 28-day mortality rate in participants aged >60 years was lower in the methylprednisolone group than in the placebo group (46.6% vs. 61.9% of participants, respectively; HR 0.63; 95% CI, 0.41–0.98; P = 0.039).
• There was no difference between the groups in the proportion of patients who were reverse transcription polymerase chain reaction (RT-PCR) positive at Day 7 (52.1% in the methylprednisolone arm and 52.6% in the placebo arm).

Safety

• Differences in the need for insulin therapy between the methylprednisolone and placebo groups were not significant (59.5% vs. 49.4% of patients, respectively; P = 0.059), nor were rates of positive blood cultures at Day 7 (8.3% vs. 8.0%, respectively), or sepsis until Day 28 (38.1% vs. 38.7% of patients, respectively).

Limitations

• This is a single-center study with a moderate sample size.
• The median days from illness onset to randomization was longer than in other corticosteroid studies.
• The high baseline mortality of this patient population may limit generalizability of the study results to populations with a lower baseline mortality.

Interpretation

The use of methylprednisolone 0.5 mg/kg twice daily for up to 5 days did not reduce 28-day mortality. In a post-hoc subgroup analysis, mortality among those aged >60 years was lower in the methylprednisolone group than in the placebo group. This study used weight-based dosing of methylprednisolone, which was approximately double the equivalent dose of dexamethasone used in the RECOVERY trial. The treatment duration was shorter (i.e., 5 days of methylprednisolone therapy vs. 10 days of dexamethasone therapy in the RECOVERY trial). Methylprednisolone is an intermediate acting corticosteroid with a shorter half-life than dexamethasone. Lastly, the median time from symptom onset to receipt of corticosteroids in this study was approximately 5 days longer than in the RECOVERY trial.

Multicenter Randomized Controlled Trial of Dexamethasone Versus Standard of Care in Patients Admitted to Intensive Care Units in Brazil

Study Design

This multicenter, randomized, open-label clinical trial conducted in 41 intensive care units (ICUs) in Brazil evaluated the use of intravenous dexamethasone (20 mg daily for 5 days, then 10 mg daily for 5 days or until ICU discharge) plus standard of care versus the standard of care alone in patients with COVID-19 and moderate to severe ARDS.¹⁷

Study Population

This study enrolled ICU patients who were receiving mechanical ventilation within 48 hours of meeting the criteria for moderate to severe ARDS (a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO₂:FiO₂] ≤ 200 mmHg).

Results

• A total of 299 patients were randomized to dexamethasone (n = 151) or the standard of care (n = 148).
• The dexamethasone group included more women than the standard of care group (40.4% vs. 34.5%), more patients with obesity (30.5% vs. 23.7%), and fewer patients with diabetes (37.8% vs. 46.6%).
• Baseline characteristics were similar for the dexamethasone and standard of care groups: mean age of 60 years versus 63 years, vasopressor use by 66% versus 68% of patients, and mean PaO₂:FiO₂ of 131 mmHg versus 133 mm Hg.
• The median time from symptom onset to randomization for both groups was 9 to 10 days; the median time from mechanical ventilation to randomization was 1 day.
• None of the patients received remdesivir; anti-IL-6 and convalescent plasma were not widely available.
• The median duration of dexamethasone therapy was 10 days (IQR 6–10 days).
• Of note, 35.1% of the patients in the standard of care group also received corticosteroids.

Study endpoints

• Primary outcome: The mean number of days alive and free from mechanical ventilation by Day 28 was higher in the dexamethasone group than in the standard of care group (6.6 days vs. 4.0 days, respectively, estimated difference of 2.3 days; 95% CI, 0.2–4.4; P = 0.04).
• Secondary outcomes: There was no difference between the groups for the following parameters:
  • All-cause mortality at Day 28 (56.3% in the dexamethasone group vs. 61.5% in the standard of care group: HR 0.97; 95% CI, 0.72–1.31; P = 0.85)
  • ICU-free days during the 28 days (dexamethasone group: mean of 2.1 days; 95% CI, 1.0–4.5 days vs. standard of care: mean of 2.0 days; 95% CI, 0.8–4.2 days; P = 0.50)
  • Duration of mechanical ventilation during the 28 days (dexamethasone group: mean of 12.5 days; 95% CI, 11.2–13.8 days vs. standard care group: mean of 13.9 days; 95% CI, 12.7–15.1 days; P = 0.11)
  • Score on 6-point WHO ordinal scale at Day 15 (median score of 5 for both groups, dexamethasone group: IQR 3–6; standard of care group: IQR 5–6; OR 0.66: 95% CI, 0.39–1.13; P = 0.07)
• The mean sequential organ failure assessment (SOFA) score at 7 days was lower in the dexamethasone group (6.1; 95% CI, 5.5–6.7) than in the standard of care group (7.5; 95% CI, 6.9–8.1) (difference -1.16; 95% CI, -1.94 to -0.38; P = 0.004).
• Post-hoc analyses
  • The dexamethasone group had a lower cumulative probability of death or mechanical ventilation at Day 15 than the standard of care group (67.5% vs. 80.4%, respectively; OR 0.46; 95% CI, 0.26–0.81; P = 0.01).
  • The proportion of patients discharged alive within 28 days was 27.8% in the dexamethasone group versus 16.9% in the standard of care group (P = 0.07).

Safety

• Safety was comparable for the dexamethasone and standard of care groups: need for insulin, 31.1% versus 28.4%; new infections, 21.9% versus 29.1%; bacteremia, 7.9% versus 9.5%; other serious adverse events, 3.3% versus 6.1%.

Limitations

• This is an open-label study.
• The study was underpowered to assess some outcomes because it stopped enrollment after data from the RECOVERY trial were released.
• During the study, 35% of the patients in the standard of care group received corticosteroids for shock, bronchospasm, or other reasons.
• Patients who were discharged from the hospital before 28 days were not followed for rehospitalization or mortality.
• The high baseline mortality of the patient population may limit generalizability of the study results to populations with a lower baseline mortality.

Interpretation

Compared with the standard of care alone, dexamethasone at a higher dose than used in the RECOVERY trial plus standard care increased the number of days alive and free of mechanical ventilation over 28 days of follow-up in patients with COVID-19 and moderate to severe ARDS. Dexamethasone was not associated with an increased risk of adverse events in this population. More than one-third of those randomized to the standard care alone group also received corticosteroids; however, it is impossible to determine the effect of corticosteroid use in these patients on the overall study outcomes.

Multicenter Randomized Controlled Trial of Hydrocortisone Versus Placebo in Patients Admitted to ICUs in France

Study Design

Community-Acquired Pneumonia: Evaluation of Corticosteroids in Coronavirus Disease (CAPE COVID) is a multicenter, randomized, double-blind, sequential trial conducted in nine French ICUs that evaluated hydrocortisone versus placebo (1:1 randomization) in patients with confirmed or suspected COVID-19 and acute respiratory failure.¹⁸

• The treatment regimen was continuous infusion hydrocortisone 200 mg/day until Day 7, then decreased to hydrocortisone 100 mg/day for 4 days, and then to hydrocortisone 50 mg/day for 3 days, for a total treatment duration of 14 days.
• Patients who showed clinical improvement by Day 4 were switched to a shorter 8-day regimen.
• The trial was embedded in a parent trial (Community-Acquired Pneumonia: Evaluation of Corticosteroids [CAPE COD]) designed to evaluate hydrocortisone therapy in severely ill ICU patients with community-acquired pneumonia.
• The planned sample size was 290 participants, but only 149 patients were enrolled because the study was terminated early following release of the results from the RECOVERY trial.

Study Population

Patients enrolled in the study had confirmed or radiographically suspected COVID-19, with at least one of four severity criteria:

• Need for mechanical ventilation with a positive end-expiratory pressure (PEEP) ≥5 cmH₂0
• High-flow oxygen with a PaO₂:FiO₂ ratio <300 mmHg and with an FiO₂ value ≥50%
• Reservoir mask oxygen with a PaO₂:FiO₂ ratio <300 mmHg (estimated)
• Pneumonia severity index >130 (scoring table)

Results

• The study enrolled 149 participants; 76 were randomized to hydrocortisone and 73 to placebo, 148 completed the study, and 149 were included in the primary (ITT) analysis.
• There was no obvious difference between the groups in baseline participant characteristics (reported by group, not overall):
  • The mean participant age was 62.2 years, 70% of the participants were men, and the median participant body mass index (BMI) was approximately 28.
  • SARS-CoV-2 infection was confirmed in 96% of the participants overall.
  • The median symptom duration before randomization was approximately 9 days in the hydrocortisone group and 10 days in the placebo group.
  • Approximately 18% of the participants had diabetes, 7% had chronic obstructive pulmonary disease or asthma, and 6% were immunosuppressed.
  • Participant baseline laboratory values were similar, including serum cortisol levels.
  • At baseline, 81% of the patients were mechanically ventilated.
  • The median systolic blood pressure was numerically higher in the placebo group than in the hydrocortisone group (127 mmHg vs. 112 mmHg).
    • At baseline, vasopressors were administered in 24% of the hydrocortisone-treated patients and 18% of the placebo-treated patients.
  • There was no difference between the groups in the use of concomitant therapies for COVID-19 at baseline (approximately 3% of participants used remdesivir, 14% used lopinavir/ritonavir, 13% used hydroxychloroquine, and 34% used hydroxychloroquine plus azithromycin).
  • The median duration of treatment was 10.5 days for hydrocortisone-treated patients versus 12.8 days for the placebo-treated patients (P = 0.25).

Study endpoints

• Primary outcome: Treatment failure (defined as death or persistent dependency on mechanical ventilation or high-flow oxygen) on Day 21 occurred in 32 of 76 patients (42.1%) in the hydrocortisone group and in 37 of 73 patients (50.7%) in the placebo group (difference of proportions -8.6%; 95% CI, -24.9% to 7.7%; P = 0.29).
• Secondary outcomes: There were no differences between the groups in the need for intubation, rescue strategies, or oxygenation (i.e., change in PaO₂:FiO₂ ratio).
  • Among the patients who did not require mechanical ventilation at baseline, 8 of 16 patients (50%) in the hydrocortisone group required subsequent intubation versus 12 of 16 patients (75%) in the placebo group.
• Post-hoc analyses
  • Clinical status on Day 21 did not significantly differ between the groups (although there were fewer deaths in the hydrocortisone group than in the placebo group [14.7% vs. 27.4%; P = 0.06]).
  • By Day 21, 57.3% of the hydrocortisone-treated patients were discharged from the ICU versus 43.8% of the placebo-treated patients.
  • By Day 21, 22.7% of the hydrocortisone-treated patients versus 23.3% of the placebo-treated patients were still mechanically ventilated.

Safety

• Apart from deaths, three serious adverse events were reported (cerebral vasculitis, cardiac arrest due to pulmonary embolism [PE], and intra-abdominal hemorrhage from anticoagulation for PE). All occurred in the hydrocortisone group; however, none were attributed to the intervention. There was no difference between the hydrocortisone and placebo groups in nosocomial infections.

Limitations

• The sample size was small.
• The study collected limited information about comorbidities (e.g., hypertension).
• The race and/or ethnicity of the study participants was not reported.
• Nosocomial infections were recorded but not adjudicated.

Interpretation

Compared to placebo, hydrocortisone does not reduce treatment failure (defined as death or persistent respiratory support) at Day 21 in ICU patients with COVID-19 and acute respiratory failure. Because this study was terminated early, it is difficult to make conclusions about the efficacy and safety of hydrocortisone therapy. The starting doses of hydrocortisone used in the CAPE COVID study were slightly higher than the 6 mg dose of dexamethasone used in the RECOVERY study. The hydrocortisone dose was adjusted according to clinical response.

Multi center International Randomized Controlled Trial Performed on an Adaptive Platform

Study Design

The Randomised, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) study used an adaptive platform trial testing multiple interventions in a pragmatic, randomized controlled trial.¹⁹

Key elements of the study design

• Randomized platform trial across 121 sites in eight countries
• Open-label comparison of multiple treatment arms within multiple therapeutic domains
• Primary analysis:
  • Includes patients with severe COVID-19
  • Bayesian cumulative logistic model adjusted for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility

Key primary outcome

• Days free of respiratory and cardiovascular organ support up to Day 21
  • The outcome assigned to patients who died was -1 day.

Key secondary outcome

• In-hospital mortality
• Need for mechanical ventilation
• Composite of progression to mechanical ventilation, extracorporeal membrane oxygenation, or death

Patient Population

• A total of 403 patients with severe COVID-19 were randomized to open-label hydrocortisone within 36 hours of ICU admission.
• Three arms were included within the corticosteroid domain:
  • Hydrocortisone 50 mg four times daily for 7 days (n = 143)
  • Septic shock-based hydrocortisone dosing (hydrocortisone 50 mg four times daily for the duration of shock; n = 152). Note that five patients in this group with unknown outcomes were removed from study analysis.
  • No hydrocortisone (n = 108)

Results

• Patient demographics for enrolled patients in the corticosteroid arms:
  • The mean age was 59.5 to 60.4 years.
  • 70.6% to 71.5% were men.
  • The mean BMI was between 29.7 and 30.9.
  • 50% to 63.5% received mechanical ventilation.
• Enrollment was halted after announcement of the RECOVERY trial results.
• There was no significant difference in mortality across the groups:
  • The median adjusted OR was 1.43 (95% credible interval, 0.91–2.27) for the fixed-duration hydrocortisone group compared to the no hydrocortisone group.
  • The median adjusted OR was 1.22 (95% credible interval, 0.76–1.94) for the shock-dependent hydrocortisone group compared to the no hydrocortisone group.
  • The model-based primary analysis included all the study arms. The analysis was repeated including only those eligible for corticosteroids, and the results were fundamentally unchanged.

Limitations

• The study was terminated early because of release of the RECOVERY study results.
• The study was randomized, but open label.

Interpretation

Corticosteroids did not significantly increase support-free days in either the fixed-dose hydrocortisone or shock-dependent hydrocortisone group, although the early termination of the trial led to limited power to detect difference between the study arms.

Retrospective Cohort Study That Compared Corticosteroids to No Corticosteroids in a Single Hospital in Shanghai, China

Study Design

This was a retrospective cohort study in patients with nonsevere COVID-19 pneumonia and propensity score-matched controls.²⁸

Study Population

• This study enrolled 475 patients with nonsevere COVID-19 pneumonia on a chest computerized tomography (CT) scan who were hospitalized at the Shanghai Public Health Clinical Center from January to June 2020. Among these patients, 55 had received early, low-dose corticosteroid therapy (50 received intravenous methylprednisolone 20 mg/day or 40 mg/day for 3 to 5 days, and five received prednisone 20 mg/day [the methylprednisolone-equivalent dose] for 3 days), and 420 did not receive any corticosteroids. Using propensity scores, 55 of the 420 patients were selected as matched controls. Study results refer to these 55 case-control pairs.
• Patients with severe pneumonia were excluded from the study. Severe pneumonia was defined as having any of the following: respiratory distress, respiratory rates >30/minute, pulse oxygen saturation <93%, oxygenation index <300 mmHg, mechanical ventilation, or shock. Patients who required immediate ICU admission at hospitalization or who used corticosteroids after progression to severe disease were also excluded from the study.

Results

• Baseline characteristics: The corticosteroid and control groups were well-matched with respect to the measured covariates. Patients in both groups had a median age of 58 to 59 years and a median oxygen saturation of 95%; 42% of the participants in the corticosteroid group and 46% in the control group had comorbidities, including 35% to 36% with hypertension and 11% to 13% with diabetes.
• Corticosteroids were administered at a median of 2 days (IQR 1–5 days) after hospital admission.
• Primary outcomes
  • Seven patients (12.7%) in the corticosteroid group developed severe disease, compared with one patient (1.8%) in the control group (P = 0.028); HR 2.2 (95% CI, 2.0 to 2.3; P < 0.001 for time to severe disease).
  • There was one death in the methylprednisolone group and none in the control group.
• Secondary outcomes: Duration of fever (5 days vs. 3 days), virus clearance time (18 days vs. 11 days), and length of hospital stay (23 days vs. 15 days) were all longer in the corticosteroid group (P < 0.001 for each outcome). More patients in the corticosteroid group than in the control group were prescribed antibiotics (89% vs. 24% of patients, respectively) and antifungal therapy (7% vs. 0% of patients, respectively).

Limitations

• This was a retrospective, case-control study.
• The sample size was small (55 case-control pairs).
• Corticosteroid therapy was selected preferentially for patients who had more risk factors for severe progression of COVID-19; the propensity score matching may not adjust for some of the unmeasured confounders.
• It is unclear if the results of this study would apply to corticosteroids other than methylprednisolone.
• Patients who used corticosteroids after progression to severe disease were excluded from the retrospective study. This exclusion requirement could introduce selection bias in favor of the control group.

Interpretation

In this study, methylprednisolone therapy in patients with nonsevere COVID-19 pneumonia was associated with worse outcomes. However, this finding is difficult to interpret because of the potential confounding factors in this nonrandomized, case-control study. It is unclear if the results for methylprednisolone therapy can be generalized to therapy with other corticosteroids.

Other Clinical Studies of Corticosteroid Use in COVID-19

Other smaller, retrospective cohort, and case-series studies have yielded conflicting results on the efficacy of corticosteroids for the treatment of COVID-19.^29-36 Several studies demonstrated the clinical benefit of using low-dose methylprednisolone early in the course of infection; the benefits included more rapid resolution of hypoxia, less need for mechanical ventilation, fewer ICU transfers, and shorter hospital stays. Additionally, other studies suggest a benefit of corticosteroids in lowering overall mortality in patients with moderate disease, severe disease, and ARDS, which is consistent with results from the RECOVERY study.

Conversely, results reported for other studies, including a meta-analysis of 15 studies in patients with coronavirus infections (e.g., COVID-19, SARS, MERS)³⁷ and a retrospective review of critically ill patients with COVID-19, suggest an increased risk of multiorgan dysfunction and no mortality benefit (and potentially an increased risk of death) with use of corticosteroids.³⁸ These study results should be interpreted with caution, as the studies are retrospective and have methodological problems.