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 Table 4a.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 Hospitalized Adults 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 Table 4a.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. Data from some of these studies can be found in Table 4a.
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).
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.
- Recovery Collaborative Group, 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131(4):954-963. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17426195.
- 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.
- 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.
- 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.
- Rezk NA, Ibrahim AM. Effects of methyl prednisolone in early ARDS. Egypt J Chest Dis Tuberc. 2013;62(1):167-172. Available at: https://www.sciencedirect.com/science/article/pii/S0422763813000265.
- 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.
- Zhao WB, Wan SX, Gu DF, Shi B. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients. Med J Chinese PLA. 2014;39(9):741-745. Available at: http://www.plamj.org/index.php/plamj/article/view/1009.
- 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.
- 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.
- Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a randomised, double-blind, phase IIb, placebo-controlled trial. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32785710.
- Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876695.
- Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876689.
- Writing Committee for the R-CAPI, Angus DC, Derde L, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876697.
- WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876694.
- Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61-98. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15634032.
- Centers for Disease Control and Prevention. Parasites - strongyloides: resources for health professionals. 2020; https://www.cdc.gov/parasites/strongyloides/health_professionals/index.html. Accessed October 30, 2020.
- Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am J Trop Med Hyg. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/32830642/.
- Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related strongyloides hyperinfection. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761166.
- Liu J, Wang T, Cai Q, et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic HBV infection. Hepatol Res. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761993.
- Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515-525. Available at: https://www.ncbi.nlm.nih.gov/pubmed/4561295.
- 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.