Corticosteroids

Last Review Performed on June 19th, 2020.

Corticosteroids inhibit a range of immune responses and therefore have broad applications in managing inflammatory disorders. Corticosteroids have previously been studied in ARDS and a limited summary of findings in that condition is included below given its relevance. Since many of the complications COVID-19 arise from inflammation, corticosteroids have been considered as a potential therapeutic option that is readily available and relatively safe at the doses discussed below.

Preliminary findings from the RECOVERY Trial were released in mid-June 2020 and showed significant 28 day mortality benefit when corticosteroids were given to patients requiring supplemental O2 or mechanical ventilation.

Given these preliminary results, peer reviewed results of some smaller studies showing benefit, as well as the relative safety and availability of corticosteroids at the dose and duration studied, use of corticosteroids in treatment of COVID-19 should be considered.

Clinical Circumstances

What severity of COVID-19 would you recommend use of this medication (i.e. mild, moderate, or severe illness; outpatient vs inpatient use)?

  • Recommended for use in admitted patients requiring supplemental O2 or mechanical ventilation

Would you recommend restricting this medication in some way (for example, “can be considered in consultation with ID”)

  • No. Use should be determined at the discretion of the primary provider.

Medication specific considerations:

Based on the current literature, what dosing is recommended?

  • 6 mg dexamethasone or equivalent (for example 40 mg prednisone for 10 days

  • No need to continue course as outpatient if discharged prior to completion of 10 day course

Is drug monitoring required? If so, what is suggested?

  • Monitor for hyperglycemia and delirium

Supply and procurement consideration: Is treatment currently available for use in our system, and if so are shortages anticipated? Are there currently restrictions or other barriers?

  • This medication is readily available at M Health Fairview - University of Minnesota Medical Center and there are no current shortages or restrictions known.

Use in special populations. Please consider use in special populations (pregnancy, immunosuppressed, kidney or liver disease, etc.) and outline any concerns below.

  • Patients with any known or suspected additional bacterial or fungal infection should be on appropriate antimicrobial therapy before initiation of steroids.

  • For pregnant women with COVID-19, avoid corticosteroids that cross the placenta (i.e. dexamethasone, betamethasone). Pregnancy is not a reason to restrict corticosteroids that do not cross the placenta (i.e. prednisolone)

Corticosteroid use in non-SARS-CoV-2 pneumonia

  1. A 2017 Cochrane review found: “Corticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits.”

    Stern A, Skalsky K, Avni T, Carrara E, Leibovici L, Paul M. Corticosteroids for pneumonia. Cochrane Database of Systematic Reviews 2017, Issue 12. Art. No.: CD007720. DOI: 10.1002/14651858.CD007720.pub3.


Corticosteroid use in ARDS:

  1. Meduri, G.U., Siemieniuk, R.A.C., Ness, R.A. et al. Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS. j intensive care 6, 53 (2018).
    An updated meta-analysis incorporating nine randomized trials (n = 816) investigating low-to-moderate dose prolonged glucocorticoid treatment in acute respiratory distress syndrome (ARDS) showed moderate-to-high quality evidence that glucocorticoid therapy is safe and

    • Reduces time to endotracheal extubation, duration of hospitalization, and mortality (number to treat to save one life = 7)

    • Increases the number of days free from mechanical ventilation, intensive care unit stay, and hospitalization.

https://doi.org/10.1186/s40560-018-0321-9

2. Villar J, Ferrando C, Martinez D et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Multicenter RCT of 17 ICUs in Spain, patients with moderate-severe ARDS. Primary outcome number of ventilator-free days at 28 days. All analyses intention-to-treat. Early administration of dexamethasone reduced duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS. Lancet Respiratory Medicine. March 1, 2020. 8 (3). p267-276.

3. Villar J, Belda J, Añón JM, et al. Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: study protocol for a randomized controlled trial. Trials. 2016;17:342. Published 2016 Jul 22. doi:10.1186/s13063-016-1456-4

Corticosteroid use in COVID-19

  1. RECOVERY Trial (press release; publication pending)

    The RECOVERY Trial is an open label randomized evaluation of COVID-19 therapy at 175 NHS hospitals in the UK. The study compares usual care alone, lopinavir-ritonavir, hydroxychloroquine, azithromycin, and corticosteroids. Eligible patients were also allocated simultaneously to no additional treatment vs. convalescent plasma. The steroid dosing was dexamethasone 6 mg/day or steroid equivalent for 10 days. Main outcomes were death, discharge, need for ventilation, and need for renal replacement therapy at 28 days. The total study has included over 11,500 patients. A total of 2104 patients were randomized to receive steroids and 4321 patients were randomized to usual care alone. A press release on 6/16/20 announced preliminary findings as follows: “Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14).”
    Press release only

  2. GLUCOCOVID trial (preprint only; publication pending)

    GLUCOCOVID partially randomized, open-label trial, multicentric trial in Spain demonstrated similar results to RECOVERY. This study compared SOC to SOC + methylprednisolone (40mg bid x 3 days then 20mg BID X 3 days). Primary composite outcome was (all cause hospital mortality, escalation to ICU, progression to respiratory insufficiency requiring non-invasive ventilation). SoC (standard of care) vs MP (methylpred). (ITT) = intention to treat. 85 patient trial.

    1. All patients composite outcome (ITT) - 48% (SoC) vs 34% (MP) - RR 0.7 (0.4-1.18)

    2. < 72 yrs old (ITT) - 40% (SoC) vs 16% (MP) - RR 0.4 (0.14 - 1.14)

    3. > 72 yrs old (ITT) - : 67% (SoC) vs 48% (MP) - RR 0.66 (0.66 - 1.11)

    4. All patients (per protocol): 48% (MP) vs 24% (MP) - RR 0.5 (0.27 - 0.94)

    5. 24% absolute reduction in primary endpoint with MP for all patients per protocol

Limitations included lower sample size, open label.

  1. Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Sig Transduct Target Ther. 2020;5(57). https://doi.org/10.1038/s41392-020-0158-2
    (human, retrospective observational study, effective)

  2. Zhou W., Liu Y., Tian D. et al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Sig Transduct Target Ther. 2020;5(18). https://doi.org/10.1038/s41392-020-0127-9 (human, observational, effective)

  3. Russell, C. D., Millar, J. E. & Baillie, J. K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. https://doi.org/10.1016/s0140-6736(20)30317-2 (2020). (human, meta-analysis, not effective)

  4. Poston JT, Patel BK, Davis AM. Management of Critically Ill Adults With COVID-19. JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4914 (human, meta-analysis, not effective)

  5. Villar J, Confalonieri M, Pastores S, Meduri G.U. Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019. Crit Care Expl. 2020; 2:e0111 doi: 10.1097/CCE.0000000000000111 (human, meta analysis/literature review/opinion, effective)

  6. Henderson, L.A., Canna, S.W., Schulert, G.S., Volpi, S., Lee, P.Y., Kernan, K.F., Caricchio, R., Mahmud, S., Hazen, M.M., Halyabar, O., Hoyt, K.J., Han, J., Grom, A.A., Gattorno, M., Ravelli, A., de Benedetti, F., Behrens, E.M., Cron, R.Q. and Nigrovic, P.A. On the alert for cytokine storm: Immunopathology in COVID‐19. Arthritis Rheumatol. 2020; Accepted Author Manuscript. doi:10.1002/art.41285 (human, literature review, effective)

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