Last Updated: August 4, 2021
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 with use of corticosteroids (mostly prednisone or methylprednisolone) in patients with pulmonary infections. In patients with Pneumocystis jirovecii pneumonia and hypoxemia, prednisone therapy reduced the risk of death.1 However, in outbreaks of previous novel coronavirus infections (i.e., Middle East respiratory syndrome [MERS] and severe acute respiratory syndrome [SARS]), corticosteroid therapy was associated with delayed virus clearance.2,3 In severe pneumonia caused by influenza viruses, corticosteroid therapy appears to result in worse clinical outcomes, including secondary bacterial infection and death.4
Corticosteroids have also been studied in critically ill patients with acute respiratory distress syndrome (ARDS) with conflicting results.5-7 Use of corticosteroids in patients with ARDS was evaluated in seven randomized controlled trials that included a total of 851 patients.6-12 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).13,14
The COVID-19 Treatment Guidelines Panel’s Recommendations for the Use of Corticosteroids in Patients with COVID-19
For nonhospitalized patients with COVID-19:
- See Therapeutic Management of Nonhospitalized Adults with COVID-19 for the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations on the use of dexamethasone or other systemic corticosteroids in certain nonhospitalized patients.
- There is insufficient evidence for the Panel to recommend either for or against the use of inhaled budesonide for the treatment of COVID-19.
For hospitalized patients with COVID-19:
- See Therapeutic Management of Hospitalized Adults with COVID-19 for the Panel’s recommendations on the use of dexamethasone or other systemic corticosteroids in certain hospitalized patients.
Rationale for Use of Corticosteroids in Patients With COVID-19
Recommendations on the use of corticosteroids for COVID-19 in nonhospitalized patients reflect a lack of data in this population. In the RECOVERY trial (described below), dexamethasone was shown to reduce mortality in hospitalized patients with COVID-19 who required supplemental oxygen. In this trial, dexamethasone was stopped at the time of hospital discharge. However, nonhospitalized patients were not included in the RECOVERY trial; thus, the safety and efficacy of corticosteroids in this population have not been established. Moreover, the use of corticosteroids can lead to adverse events (e.g., hyperglycemia, neuropsychiatric symptoms, secondary infections), which may be difficult to detect and monitor in an outpatient setting (see General Management of Nonhospitalized Patients With Acute COVID-19 for further information).
Recommendations on the use of corticosteroids for COVID-19 in hospitalized patients are largely based on data from the RECOVERY trial, a large, multicenter, open-label randomized trial performed in the United Kingdom. This trial randomized 6,425 hospitalized patients to receive up to 10 days of dexamethasone or standard of care. Mortality at 28 days was lower among the patients who received dexamethasone than among those who received the standard of care.15 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 from the RECOVERY trial are discussed in Table 4a.15
Systemic corticosteroids used in combination with other agents including antivirals and immunomodulators such as tocilizumab (see Interleukin-6 Inhibitors)16,17 or baricitinib (see Kinase Inhibitors)18 have demonstrated clinical benefit in subsets of hospitalized patients with COVID-19.
Systemic corticosteroids used in various formulations and doses for varying durations have been studied in patients with COVID-19 in several smaller randomized controlled trials.19-23 Some of these trials were stopped early due to under enrollment following the release of the results from the RECOVERY trial. Consequently, the sample size of many these trials was insufficient to assess efficacy, and therefore evidence to support the use of methylprednisolone and hydrocortisone for the treatment of COVID-19 is not as strong as that demonstrated for dexamethasone in the RECOVERY trial.
Systemic Corticosteroids Other Than Dexamethasone
- If dexamethasone is not available, alternative glucocorticoids (e.g., prednisone, methylprednisolone, hydrocortisone) can be used.
- For these drugs, the total daily dose equivalencies to dexamethasone 6 mg (oral or intravenous)24 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 Hemodynamics 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.9
Budesonide is a synthetic, inhaled corticosteroid with potent glucocorticoid activity and weak mineralocorticoid activity. It has broad anti-inflammatory properties and has Food and Drug Administration-labeled indications in the management of chronic respiratory diseases including asthma and chronic obstructive pulmonary disease. Certain inhaled corticosteroids have been shown to impair viral replication of SARS-CoV-225 and downregulate expression of the receptors used for cell entry.26,27 These mechanisms support the potential of inhaled corticosteroids as therapeutic agents for COVID-19. However, observational studies of individuals who were chronic inhaled corticosteroid users have found that its use either had no effect on COVID-19 outcomes or increased risk of hospitalization.28,29
There is insufficient evidence for the Panel to recommend either for or against the use of inhaled budesonide for the treatment of COVID-19.
Inhaled budesonide was studied in two open-label trials in outpatients with mild symptoms of COVID-19 (see Table 4b).30,31 Results of these trials suggest that in adult outpatients with mild COVID-19, initiation of inhaled budesonide may reduce the need for urgent care or emergency department assessment or hospitalization and reduce time to recovery. The findings from these trials should be interpreted with caution given the open-label design of the studies, incomplete data, and other limitations. Additional trials of inhaled corticosteroids are ongoing.
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).
- The use of systemic corticosteroids may increase the risk of opportunistic fungal infections (e.g., mucormycosis, aspergillosis) and reactivation of latent infections (e.g., hepatitis B virus [HBV], herpesvirus infections, strongyloidiasis, tuberculosis).32-35 When initiating dexamethasone, clinicians should consider 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)36-38 or fulminant reactivations of HBV.39
- Combining systemic corticosteroids with other immunosuppressants, such as tocilizumab or baricitinib, could theoretically increase the risk of secondary infections. However, this adverse effect has not been reported in clinical trials to date.
- 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.
- Dexamethasone should be continued for up to 10 days or until hospital discharge, whichever comes first (see Therapeutic Management of Hospitalized Adults With COVID-19).
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.40,41
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 patients 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 and caution is warranted when extrapolating recommendations for adults to patients aged <18 years. The Panel recommends using dexamethasone for children with COVID-19 who require high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (BIII). Corticosteroids are not routinely recommended for pediatric patients who require only low levels of oxygen support (i.e., administered via a nasal cannula only). Use of dexamethasone for the treatment of severe COVID-19 in children who are profoundly immunocompromised has not been evaluated and may be harmful; therefore, such use should be considered only on a case-by-case basis. The dexamethasone dosing regimen for pediatric patients is dexamethasone 0.15 mg/kg/dose (maximum dose 6 mg) once daily for up to 10 days. Corticosteroid use has been described in the treatment of multisystem inflammatory syndrome in children (MIS-C) in multiple case series. It is the second most used therapy after intravenous immunoglobulin for MIS-C.42,43 Please refer to Special Considerations in Children for more information on the management of MIS-C.
Several clinical trials evaluating corticosteroids for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.
- 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. Egyptian Journal of Chest Diseases and Tuberculosis. 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. 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.
- 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.
- RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2021;384(8):693-704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
- RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33933206.
- REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021;384(16):1491-1502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.
- Marconi VC, Ramanan AV, de Bono S, et al. Baricitinib plus standard of care for hospitalized adults with COVID-19. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.04.30.21255934v1.
- Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID-19; Metcovid): a randomized, double-blind, Phase IIb, placebo-controlled trial. Clin Infect Dis. 2021 May 4;72(9):e373-e381. 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;324(13):1307-1316. 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;324(13):1298-1306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876689.
- Angus DC, Derde L, Al-Beidh F, 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;324(13):1317-1329. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876697.
- WHO Rapid Evidence Appraisal for COVID-19 Therapies 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;324(13):1330-1341. 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.
- Matsuyama S, Kawase M, Nao N, et al. The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting the viral replication-transcription complex in cultured cells. J Virol. 2020;95(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33055254.
- Finney LJ, Glanville N, Farne H, et al. Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon. J Allergy Clin Immunol. 2021;147(2):510-519 e515. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33068560.
- Peters MC, Sajuthi S, Deford P, et al. COVID-19-related genes in sputum cells in asthma. Relationship to demographic features and corticosteroids. Am J Respir Crit Care Med. 2020;202(1):83-90. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32348692.
- Choi JC, Jung SY, Yoon UA, et al. Inhaled corticosteroids and COVID-19 risk and mortality: a nationwide cohort study. J Clin Med. 2020;9(11). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33114246.
- Schultze A, Walker AJ, MacKenna B, et al. Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform. Lancet Respir Med. 2020;8(11):1106-1120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32979987.
- Ramakrishnan S, Nicolau DV, Jr., Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a Phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33844996.
- PRINCIPLE Collaborative Group, Yu L, Bafadhel M, et al. Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.04.10.21254672v1.
- Garg D, Muthu V, Sehgal IS, et al. Coronavirus Disease (COVID-19) associated mucormycosis (CAM): case report and systematic review of literature. Mycopathologia. 2021;186(2):289-298. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33544266.
- Moorthy A, Gaikwad R, Krishna S, et al. SARS-CoV-2, Uncontrolled diabetes and corticosteroids-an unholy trinity in invasive fungal infections of the maxillofacial region? A retrospective, multi-centric analysis. J Maxillofac Oral Surg. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33716414.
- Machado M, Valerio M, Alvarez-Uria A, et al. Invasive pulmonary aspergillosis in the COVID-19 era: an expected new entity. Mycoses. 2021;64(2):132-143. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33210776.
- Chauvet P, Mallat J, Arumadura C, et al. Risk factors for invasive pulmonary aspergillosis in critically ill patients with coronavirus disease 2019-induced acute respiratory distress syndrome. Crit Care Explor. 2020;2(11):e0244. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33205046.
- Centers for Disease Control and Prevention. Parasites—strongyloides: resources for health professionals. 2020. Available at: https://www.cdc.gov/parasites/strongyloides/health_professionals/index.html. Accessed July 27, 2021.
- Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am J Trop Med Hyg. 2020;103(4):1590-1592.. 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;324(7):623-624. 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;50(11):1211-1221. 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.
- Ouldali N, Toubiana J, Antona D, et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA. 2021;325(9):855-864. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33523115.
- Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children—initial therapy and outcomes. N Engl J Med. 2021;385(1):23-34. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34133855.