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Corticosteroids

Last Updated: July 30, 2020

Recommendations for Patients with COVID-19

  • On the basis of the preliminary report from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial (discussed below), the COVID-19 Treatment Guidelines Panel (the Panel) recommends using dexamethasone 6 mg per day for up to 10 days for the treatment of COVID-19 in patients who are mechanically ventilated (AI) and in patients who require supplemental oxygen but who are not mechanically ventilated (BI).
  • The Panel recommends against using dexamethasone for the treatment of COVID-19 in patients who do not require supplemental oxygen (AI).
  • If dexamethasone is not available, the Panel recommends using alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone (see Additional Considerations below for dosing recommendations) (AIII).

Rationale

RECOVERY, a multicenter, randomized, open-label trial in hospitalized patients with COVID-19, showed that the mortality rate was lower among patients who were randomized to receive dexamethasone than among those who received standard of care (SOC).1 This benefit was observed in patients who required supplemental oxygen at enrollment. No benefit of dexamethasone was seen in patients who did not require supplemental oxygen at enrollment. Details of the trial are discussed in the Clinical Data to Date section below.1

Proposed Mechanism of Action and Rationale for Use in Patients with COVID-19

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. Both beneficial and deleterious clinical outcomes have been reported when corticosteroids (mostly prednisone or methylprednisolone) were used in patients with other pulmonary infections. In patients with Pneumocystis jirovecii pneumonia and hypoxia, prednisone therapy led to decreased mortality;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, corticosteroid therapy appears to result in worse clinical outcomes, including secondary bacterial infection and mortality.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 851 patients evaluated use of corticosteroids in ARDS.7-13 However, when the trial results were combined by meta-analysis, corticosteroid therapy was associated with a reduction in both mortality (risk ratio 0.75; 95% confidence interval [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

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, herpesvirus infections, strongyloidiasis, tuberculosis).
  • 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 regimens to assess potential interactions.
  • Coadministration of remdesivir and dexamethasone has not been formally studied, but a clinically significant pharmacokinetic interaction is not predicted.

Additional Considerations

  • Whether use of other corticosteroids (e.g., prednisone, methylprednisolone, hydrocortisone) for the treatment of COVID-19 provides the same benefit as dexamethasone is unclear. The total daily dose equivalencies to dexamethasone 6 mg (oral or intravenous [IV])16 for these drugs 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; please refer to the Critical Care section for more information. Unlike other corticosteroids previously studied in ARDS, dexamethasone lacks mineralocorticoid activity and thus has minimal effect on sodium balance and fluid volume.10

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.17,18

Given the potential benefit of decreased maternal mortality, and the low risk of fetal adverse effects for this short course of therapy, the Panel recommends using dexamethasone in 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 rates are significantly lower among pediatric patients with COVID-19 than among adult patients with the disease. Thus, caution is warranted when extrapolating the results of this trial to patients aged <18 years. Dexamethasone may be beneficial in pediatric patients with COVID-19 respiratory disease who are on 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 in those with multisystem inflammatory syndrome in children (MIS-C).

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 SOC or SOC alone. In one of the study arms, dexamethasone 6 mg daily was administered either orally or IV for 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.1

Study Population

Hospitalized patients in the United Kingdom with clinically suspected COVID-19 or laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (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 definitely indicated. Recruitment into the dexamethasone arm was stopped by the study steering committee on June 8, 2020, when enough participants were enrolled to assess benefit.

Preliminary Results

Participant Characteristics:

  • The preliminary analysis included 6,425 participants, with 2,104 participants in the dexamethasone arm and 4,321 in the SOC alone arm.
  • SARS-CoV-2 infection was confirmed by laboratory testing in 89% of the participants.
  • The mean age of the participants was 66.1 years, 64% of participants were male, and 56% had at least one major comorbidity, including 24% who had diabetes.
  • At enrollment, 16% of participants required invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% had received supplemental oxygen but no invasive ventilation, and 24% required no oxygen supplementation.
  • Few participants received remdesivir, hydroxychloroquine, lopinavir/ritonavir, or tocilizumab (0% to 3% of participants in both arms); approximately 8% of participants in the SOC alone arm received dexamethasone after randomization. Use of azithromycin was balanced in both arms (24% in the dexamethasone arm vs. 25% in the SOC alone arm).

Study Endpoint Analyses:

  • Overall, 22.9% of participants in the dexamethasone arm and 25.7% of those in the SOC alone arm died within 28 days of study enrollment (age-adjusted rate ratio [RR] 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 of enrollment compared with 41.4% of those in the SOC alone arm (RR 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 died within 28 days of enrollment compared with 26.2% of those in the SOC alone arm (RR 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 died within 28 days of enrollment compared with 14.0% of those in the SOC alone arm (RR 1.19; 95% CI, 0.91–1.55).
  • The risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the SOC alone group (RR 0.77; 95% CI, 0.62–0.95).
  • Results for several secondary endpoints (e.g., cause-specific mortality, need for renal replacement, major cardiac arrhythmia) have not yet been reported.

Limitations

  • The study was randomized, but open label.
  • At this time, the results for key secondary endpoints, 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, according to their providers, required oxygen but not mechanical ventilation were a heterogeneous group of patients with respect to their severity of illness; it is unclear whether use of dexamethasone will be beneficial for other participant subsets (e.g., those who require lower rather than higher levels of supplemental oxygen). There were also no standardized or objective criteria for oxygen supplementation.
  • The age distribution of participants differed by respiratory status at randomization. The participants who received mechanical ventilation were more likely to be aged <70 years. Among the participants who were aged >80 years, only 1% were mechanically ventilated, while 62% and 37% were in the oxygen group and no oxygen group, respectively. Therefore, the survival benefit of dexamethasone for mechanically ventilated patients aged >80 years is unknown.
  • Remdesivir was used in only five patients in the RECOVERY trial; therefore, the safety and efficacy of coadministering remdesivir and dexamethasone are not known.
  • Very few pediatric or pregnant patients with COVID-19 were included in the RECOVERY trial; therefore, the safety and efficacy of using dexamethasone in these patients are unknown.

Interpretation

In patients with severe COVID-19 who required oxygen support, the use of dexamethasone 6 mg daily for up to 10 days reduced mortality at 28 days in a preliminary analysis. The benefit of dexamethasone was most apparent in hospitalized patients who were mechanically ventilated. There was no observed benefit of dexamethasone in those not requiring oxygen support. Further clarity on the mortality benefit of dexamethasone by baseline levels of oxygenation, age, sex, comorbidities, and/or duration of symptoms would better inform application of these findings. More details regarding safety of dexamethasone and longer follow-up would assist in interpretation of this study.

Other Clinical Studies of Corticosteroids in COVID-19

Smaller retrospective cohort and case series studies have yielded conflicting results on the efficacy of corticosteroids for the treatment of COVID-19.19 Several studies demonstrated clinical benefit with use of low-dose methylprednisolone early in infection, including more rapid resolution of hypoxia, less need for mechanical ventilation, fewer intensive care unit transfers, and shorter hospital stays.20 Additionally, other studies revealed a benefit in lower overall mortality in patients with moderate disease, severe disease, and ARDS,21-24 consistent with results from the RECOVERY study.

Conversely, results reported for other studies, including a meta-analysis of 15 studies (which included studies for treatment of COVID-19, SARS, or MERS)25 and a retrospective review of critically ill patients with COVID-19, suggest an increased risk of multi-organ dysfunction and no benefit in (and potentially an increased risk of) mortality with use of corticosteroids.26

These study results should be interpreted with caution as the studies are retrospective in nature and have methodological problems.

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.

References

  1. Group RC, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
  2. Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. 1990;323(21):1451-1457. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2233917.
  3. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29161116.
  4. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16968120.
  5. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26950335.
  6. Meduri GU, Bridges L, Shih MC, Marik PE, Siemieniuk RAC, Kocak M. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med. 2016;42(5):829-840. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26508525.
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  8. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16625008.
  9. Liu L, Li J, Huang YZ, et al. The effect of stress dose glucocorticoid on patients with acute respiratory distress syndrome combined with critical illness-related corticosteroid insufficiency. Zhonghua Nei Ke Za Zhi. 2012;51(8):599-603. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23158856.
  10. Villar J, Ferrando C, Martinez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32043986.
  11. Rezk NA, Ibrahim AM. Effects of methyl prednisolone in early ARDS. Egyptian Journal of Chest Diseases and Tuberculosis. 2013;62(1):167-172. Available at: https://www.sciencedirect.com/science/article/pii/S0422763813000265.
  12. Tongyoo S, Permpikul C, Mongkolpun W, et al. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care. 2016;20(1):329. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27741949.
  13. Zhao WB, Wan SX, Gu DF, Shi B. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients. Medical Journal of Chinese People's Liberation Army. 2014;39(9):741-745. Available at: http://www.plamj.org/index.php/plamj/article/view/1009.
  14. Mammen MJ, Aryal K, Alhazzani W, Alexander PE. Corticosteroids for patients with acute respiratory distress syndrome: a systematic review and meta-analysis of randomized trials. Pol Arch Intern Med. 2020;130(4):276-286. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32186831.
  15. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32224769.
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  18. Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al. Antenatal betamethasone for women at risk for Late Preterm Delivery. N Engl J Med. 2016;374(14):1311-1320. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26842679.
  19. Keller MJ, Kitsis EA, Arora S, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. Journal of Hospital Medicine. 2020;15(8):489-493. Available at: https://www.journalofhospitalmedicine.com/jhospmed/article/225402/hospital-medicine/effect-systemic-glucocorticoids-mortality-or-mechanical.
  20. Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther. 2020;5(1):57. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32341331.
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  22. Corral L, Bahamonde A, Arnaiz delas Revillas F, et al. GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. medRxiv. 2020. Available at: https://www.medrxiv.org/content/10.1101/2020.06.17.20133579v1.
  23. Fadel R, Morrison AR, Vahia A, et al. Early short course corticosteroids in hospitalized patients with COVID-19. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32427279.
  24. Fernandez Cruz A, Ruiz-Antoran B, Munoz Gomez A, et al. Impact of glucocorticoid treatment in SARS-CoV-2 infection mortality: a retrospective controlled cohort study. Antimicrob Agents Chemother. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32571831.
  25. Yang Z, Liu J, Zhou Y, Zhao X, Zhao Q, Liu J. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect. 2020;81(1):e13-e20. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32283144.
  26. Lu X, Chen T, Wang Y, Wang J, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. Crit Care. 2020;24(1):241. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32430057.