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Corticosteroids

Last Updated: October 19, 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, during 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 patients with severe pneumonia caused by influenza viruses, corticosteroid therapy appears to result in worse clinical outcomes, including secondary bacterial infections and death.4

Corticosteroid therapy has 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 the duration of mechanical ventilation (mean difference -4.93 days; 95% CI, -7.81 to -2.06 days).13,14

Corticosteroid use for the treatment of COVID-19 has been studied in clinical trials (see Tables 4a and 4b for more information). The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the use of corticosteroids in patients with COVID-19 are based on the results from these studies.

Recommendations

For nonhospitalized patients with COVID-19:

  • See Therapeutic Management of Nonhospitalized Adults with COVID-19 for the Panel’s 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:

Rationale

The Panel’s recommendations on the use of corticosteroids for COVID-19 in nonhospitalized patients reflect a lack of data regarding their use 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; however, treatment with dexamethasone was stopped at the time of hospital discharge. Because nonhospitalized patients were not included in the RECOVERY trial, the safety and efficacy of corticosteroid use for COVID-19 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 Therapeutic Management of Nonhospitalized Adults With COVID-19).

The Panel’s recommendations on the use of corticosteroids for COVID-19 in hospitalized patients are largely based on data from the RECOVERY trial. This large, multicenter, open-label randomized controlled trial performed in the United Kingdom randomized 6,425 hospitalized patients to receive up to 10 days of dexamethasone plus the standard of care or the standard of care only. Mortality at Day 28 was lower among the patients who received dexamethasone than among those who received the standard of care alone.15 This mortality 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 summarized in Table 4d.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.

Various formulations of systemic corticosteroids used in different 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.

Please see Tables 4a and 4b for data from clinical trials that have evaluated corticosteroid use for the treatment of COVID-19.

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 [IV])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

Inhaled Corticosteroids

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 for 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 have found that long-term use of inhaled corticosteroids prescribed for non-COVID-19 respiratory diseases either had no effect on COVID-19 outcomes or increased the risk of hospitalization.28,29 More recently, two open-label randomized controlled trials provided additional insights regarding the role of inhaled budesonide in outpatients with COVID-19, as described below and in Table 4b.

Recommendation

There is insufficient evidence for the Panel to recommend either for or against the use of inhaled budesonide for the treatment of COVID-19.

Rationale

Inhaled budesonide was studied in two open-label randomized controlled trials in outpatients with mild symptoms of COVID-19.30,31 The small STOIC trial suggested 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.30 PRINCIPLE, a larger open-label trial in nonhospitalized patients with COVID-19 at high risk of disease progression, found that inhaled budesonide did not affect the rate of hospitalization or death but did reduce time to self-reported recovery.31 The findings from these trials should be interpreted with caution given the open-label design of the studies and other limitations as outlined in the study description in Table 4b. Additional trials of inhaled corticosteroids are ongoing.

Most of the patients included in the PRINCIPLE trial would also have been candidates for anti-SARS-CoV-2 monoclonal antibody (mAb) therapy, which has been shown to reduce the risk of hospitalization and death in patients who have mild to moderate COVID-19 and certain risk factors for disease progression. Whether inhaled budesonide provides any additional benefit for patients who have received anti-SARS-CoV-2 mAb therapy is unknown.

Monitoring, Adverse Effects, and Drug-Drug Interactions for Systemic Corticosteroids

  • 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, herpesvirus infections, strongyloidiasis, tuberculosis).32-36
  • Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with tocilizumab and corticosteroids.37,38 Many clinicians would initiate empiric treatment for strongyloidiasis (e.g., with ivermectin) with or without serologic testing in patients from areas where Stronglyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).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 or 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 for 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 IV immunoglobulin for MIS-C.42,43 Please refer to Special Considerations in Children for more information on the management of MIS-C.

Clinical Trials

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.

References

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