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Systemic Corticosteroids

Last Updated: February 29, 2024

The results of several randomized trials indicate that systemic corticosteroid therapy improves clinical outcomes and reduces mortality in hospitalized patients with COVID-19 who require supplemental oxygen,1,2 presumably by mitigating the COVID-19–induced systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction. In contrast, in hospitalized patients with COVID-19 who do not require supplemental oxygen, the use of systemic corticosteroids provided no benefit and increased mortality.3,4 The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the use of systemic corticosteroids in hospitalized patients with COVID-19 are based on results from these clinical trials (see Table 5a). There are no data to support the use of systemic corticosteroids in nonhospitalized patients with COVID-19.

Recommendations

  • The Panel recommends against the use of dexamethasone or other systemic corticosteroids to treat outpatients with mild to moderate COVID-19 who do not require hospitalization or supplemental oxygen (AIIb).
  • 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 with COVID-19.
  • Patients with COVID-19 who are receiving dexamethasone or another corticosteroid for an underlying condition should continue this therapy as directed by their health care provider (AIII).

Rationale

Nonhospitalized Adults

There are no data to support the use of systemic corticosteroids in nonhospitalized patients with COVID-19. Therefore, the safety and efficacy of using systemic corticosteroids in this population have not been established. Generally, the use of systemic corticosteroids is associated with adverse events (e.g., hyperglycemia, neuropsychiatric symptoms, secondary infections), which may be difficult to detect and monitor in an outpatient setting. For more information, see Therapeutic Management of Nonhospitalized Adults With COVID-19

Hospitalized Adults

The RECOVERY trial was a multicenter, open-label trial in the United Kingdom that randomly assigned 6,425 hospitalized patients to receive up to 10 days of dexamethasone 6 mg once daily plus standard care or standard care alone.3 Mortality at 28 days was lower among the patients who received dexamethasone than among those who received standard care alone. This benefit of dexamethasone was observed in patients who were mechanically ventilated or who required supplemental oxygen at enrollment. In contrast, no benefit was seen in patients who did not require supplemental oxygen at enrollment.

Several clinical trials have evaluated the use of systemic corticosteroids in critically ill patients with COVID-19 who were on supplemental oxygen with or without mechanical ventilation. These trials reported that all-cause mortality at 28 days was lower in those who received systemic corticosteroids than in those who received standard of care or placebo; however, some of these trials were terminated early.1 

In addition to the randomized controlled trials, a large observational study evaluated the use of systemic corticosteroids in 15,404 hospitalized patients with positive SARS-CoV-2 polymerase chain reaction or antigen test results from a Department of Veterans Affairs database.4 Corticosteroids were administered to 60% of the patients within 48 hours of admission, and 95% of the patients who received corticosteroids received dexamethasone. A total of 9,450 patients did not receive supplemental oxygen during the study. Of these patients, 3,514 (37%) received dexamethasone for a median duration of 5 days (IQR 3–8 days). Using average treatment effect estimates, patients who received dexamethasone without supplemental oxygen had an increased risk of death within 90 days (HR 1.76; 95% CI, 1.47–2.12). Patients who received dexamethasone either without supplemental oxygen or with low-flow nasal cannula oxygen had a 60% higher risk of death. Although this study was observational, the investigators employed several statistical techniques to minimize potential bias, including propensity scoring and weighted analyses. Additionally, several subgroup and sensitivity analyses in this study confirmed the overall results.

Dexamethasone Dose

The RECOVERY platform trial studied the use of dexamethasone 6 mg once daily for up to 10 days,3 which is currently the recommended dose for hospitalized adults with COVID-19 who require supplemental oxygen. Several other randomized controlled trials evaluated the role of higher doses of dexamethasone or other corticosteroids in hospitalized patients with different levels of respiratory support. The results of some key studies are summarized below.

Patients Who Received Conventional Oxygen or No Supplemental Oxygen

The RECOVERY platform trial included an additional study in which patients with COVID-19 and evidence of hypoxemia (i.e., they were receiving conventional supplemental oxygen or had an oxygen saturation <92% on room air) were randomized to receive usual care plus high-dose dexamethasone (20 mg once daily for 5 days, then 10 mg once daily for 5 days or until hospital discharge, whichever came first) or usual care alone, which included low-dose dexamethasone (usually 6 mg once daily for 10 days).5 On May 11, 2022, the trial’s independent data monitoring committee stopped enrolling patients receiving conventional oxygen therapy and those not receiving any supplemental oxygen. Among the 1,272 patients enrolled, 28-day mortality was higher in the high-dose dexamethasone arm than in the usual care arm (19% vs. 12%; rate ratio 1.59; 95% CI, 1.20–2.10; P = 0.0012). 

Patients Who Received Noninvasive or Mechanical Ventilation

The COVID STEROID 2 trial investigated the use of different doses of corticosteroids in patients with COVID-19 and severe hypoxemia.6 In this multicenter trial, hospitalized patients who required at least 10 L/min of oxygen or mechanical ventilation were randomized to receive up to 10 days of dexamethasone 6 mg once daily (n = 485) or dexamethasone 12 mg once daily (n = 497). The median number of days alive without life support at 28 days after randomization was 20.5 days in the dexamethasone 6 mg arm and 22.0 days in the dexamethasone 12 mg arm, yielding an adjusted mean difference of 1.3 days (95% CI, 0–2.6; P = 0.07). No differences between the arms were found for 28- or 90-day mortality. Although these conventional analyses did not quite reach statistical significance, a preplanned Bayesian analysis found that dexamethasone 12 mg had a higher probability of benefit and a lower probability of harm than dexamethasone 6 mg.7 

In the COVIDICUS trial, patients with COVID-19 and acute hypoxemic respiratory failure were randomized to receive dexamethasone 6 mg once daily for 10 days (n = 276, of which 37 received placebo prior to release of results from the RECOVERY trial)3 or high-dose dexamethasone (i.e., 20 mg once daily for 5 days, then 10 mg once daily for 5 days; n = 270).8 At baseline, 98 patients were receiving mechanical ventilation, 114 were receiving continuous positive airway pressure, 10 were receiving noninvasive ventilation (NIV), 199 were receiving high-flow nasal cannula oxygen, and 125 were receiving standard oxygen therapy through a nonrebreather mask. There was no difference in 60-day mortality between the arms (HR 0.96; 95% CI, 0.69–1.33; P = 0.79).

The mixed results from these studies have led the Panel to continue to recommend 6 mg once daily as the preferred dose of dexamethasone in hospitalized patients with COVID-19 who require supplemental oxygen, including patients receiving NIV or mechanical ventilation. However, the Panel notes that both the conventional and Bayesian analyses conducted during the COVID STEROID 2 trial suggest that a dose of 12 mg might confer a benefit in patients who require NIV or mechanical ventilation.6,7 Most patients in the COVID STEROID 2 trial did not receive additional immunomodulators beyond corticosteroids.6 Currently, there are no data from clinical trials that evaluated the safety and efficacy of using doses of dexamethasone that were larger or smaller than 6 mg once daily in combination with other immunomodulators to treat hospitalized adults with COVID-19. 

Combination Immunomodulator Therapy

Using systemic corticosteroids in combination with other agents, including tocilizumab (see Interleukin-6 Inhibitors),9,10 baricitinib (see Janus Kinase Inhibitors),11 abatacept, or infliximab,12 has been shown to have a clinical benefit in subsets of hospitalized patients with COVID-19, especially those who are in the early stages of critical illness and those with signs of systemic inflammation. For the Panel’s recommendations on when to use dexamethasone with another immunomodulator, see Therapeutic Management of Hospitalized Adults With COVID-19.

See Table 5a for a summary of the data from clinical trials that have evaluated the use of systemic corticosteroids in patients with COVID-19. 

Systemic Corticosteroids Other Than Dexamethasone

Systemic corticosteroids other than dexamethasone, including hydrocortisone13,14 and methylprednisolone,15,16 have been studied for the treatment of COVID-19 in several randomized trials. Some of these trials were stopped early due to low enrollment following the release of the RECOVERY trial results. Consequently, the sample size of these trials was insufficient to assess efficacy (i.e., there were too few events to definitively confirm or exclude an effect, although many point estimates suggested a beneficial effect). Therefore, the evidence supporting the use of hydrocortisone or methylprednisolone for the treatment of COVID-19 is not as strong as the evidence supporting the use of dexamethasone. Based on the available evidence, the Panel has concluded the following:

  • If dexamethasone is not available, alternative corticosteroids (e.g., prednisone, methylprednisolone, hydrocortisone) can be used (BIII)
  • For these drugs, the total daily dose equivalencies to dexamethasone 6 mg (orally or intravenously)17 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-lives 12 to 36 hours; administer once daily or in 2 divided doses daily.
    • Short-acting corticosteroid: Hydrocortisone; half-life 8 to 12 hours; administer in 2 to 4 divided doses daily.
  • Hydrocortisone is commonly used to manage septic shock in patients with COVID-19; see Hemodynamics for Adults for more information. Unlike other corticosteroids that have previously been studied in patients with acute respiratory distress syndrome, dexamethasone lacks mineralocorticoid activity and, thus, its effects on sodium balance and fluid volume are minimal.18

Monitoring, Adverse Effects, and Drug-Drug Interactions

Clinicians should closely monitor patients with COVID-19 who are receiving dexamethasone for certain 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., aspergillosis, mucormycosis) and reactivation of latent infections (e.g., hepatitis B virus infection,  herpes simplex virus and varicella zoster virus infections, strongyloidiasis, tuberculosis).19-26 Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with tocilizumab and corticosteroids.24,27 Many clinicians would initiate empiric treatment for strongyloidiasis (e.g., with the antiparasitic drug ivermectin), with or without serologic testing, in patients who currently reside or who have previously resided in areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).28 

Using systemic corticosteroids with other immunosuppressants, such as tocilizumab or baricitinib, could theoretically increase the risk of secondary infections. However, clinical trials have reported no difference in the rates of secondary infections between patients who received corticosteroids in combination with another immunomodulatory agent and those who received corticosteroids alone. Dexamethasone is a moderate cytochrome P450 3A4 inducer. Therefore, it could reduce the concentration and potential efficacy of concomitant medications that are cytochrome P450 3A4 substrates. Clinicians should carefully review a patient’s concomitant medications to assess the potential for drug-drug interactions.

Considerations in Pregnant and Lactating People

See Pregnancy, Lactation, and COVID-19 Therapeutics for the Panel’s guidance regarding the use of dexamethasone during pregnancy and lactation. 

Considerations in Children

Dexamethasone is recommended for hospitalized children with COVID-19 who require supplemental oxygen. See Therapeutic Management of Hospitalized Children With COVID-19 for the Panel’s recommendations. Methylprednisolone or another corticosteroid is recommended for the treatment of multisystem inflammatory syndrome in children (MIS-C). See Therapeutic Management of Hospitalized Children With MIS-C, Plus a Discussion on MIS-A for the Panel’s recommendations.

References

  1. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. 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.
  2. Li H, Yan B, Gao R, Ren J, Yang J. Effectiveness of corticosteroids to treat severe COVID-19: a systematic review and meta-analysis of prospective studies. Int Immunopharmacol. 2021;100:108121. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34492533.
  3. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med . 2021;384(8):693-704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
  4. Crothers K, DeFaccio R, Tate J, et al. Dexamethasone in hospitalised COVID-19 patients not on intensive respiratory support. Eur Respir J. 2022;60(1):2102532. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34824060.
  5. RECOVERY Collaborative Group. Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2023;401(10387):1499-1507. Available at: https://pubmed.ncbi.nlm.nih.gov/37060915.
  6. COVID STEROID 2 Trial Group. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. JAMA. 2021;326(18):1807-1817. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34673895.
  7. Granholm A, Munch MW, Myatra SN, et al. Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial. Intensive Care Med. 2022;48(1):45-55. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34757439.
  8. Bouadma L, Mekontso-Dessap A, Burdet C, et al. High-dose dexamethasone and oxygen support strategies in intensive care unit patients with severe COVID-19 acute hypoxemic respiratory failure: the COVIDICUS randomized clinical trial. JAMA Intern Med. 2022;182(9):906-916. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35788622.
  9. 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.
  10. REMAP-CAP Investigators. 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.
  11. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled Phase 3 trial. Lancet Respir Med. 2021;9(12):1407-1418. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34480861.
  12. O'Halloran JA, Ko ER, Anstrom KJ, et al. Abatacept, cenicriviroc, or infliximab for treatment of adults hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA. 2023;330(4):328-339. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37428480.
  13. 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.
  14. 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.
  15. Corral-Gudino L, Bahamonde A, Arnaiz-Revillas F, et al. Methylprednisolone in adults hospitalized with COVID-19 pneumonia: an open-label randomized trial (GLUCOCOVID). Wien Klin Wochenschr. 2021;133(7-8):303-311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33534047.
  16. Tang X, Feng YM, Ni JX, et al. Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit patients with COVID-19 pneumonia: a multicenter, single-blind, randomized control trial. Respiration. 2021;100(2):116-126. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33486496.
  17. Czock D, Keller F, Rasche FM, Häussler 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.
  18. Villar J, Ferrando C, Martínez 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.
  19. 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://pubmed.ncbi.nlm.nih.gov/33544266.
  20. 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;20(3):418-425. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33716414.
  21. Machado M, Valerio M, Álvarez-Uría 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.
  22. 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.
  23. 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 hepatitis B virus infection. Hepatol Res. 2020;50(11):1211-1221. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761993.
  24. Lier AJ, Tuan JJ, 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://www.ncbi.nlm.nih.gov/pubmed/32830642.
  25. Garg N, Lee YI. Reactivation TB with severe COVID-19. Chest. 2020;158(4):A777. Available at: https://journal.chestnet.org/article/S0012-3692(20)32910-X/fulltext.
  26. Xu R, Zhou Y, Cai L, et al. Co-reactivation of the human herpesvirus alpha subfamily (herpes simplex virus-1 and varicella zoster virus) in a critically ill patient with COVID-19. Br J Dermatol. 2020;183(6):1145-1147. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32790074.
  27. Marchese V, Crosato V, Gulletta M, et al. Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. Infection. 2021;49(3):539-542. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32910321.
  28. 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.