Dexamethasone in Patients Hospitalized for COVID-19

Background

In some people, infection with SARS-CoV-2, the virus causing COVID-19, triggers an overreaction of the immune system that can result in severe injury to a number of organs including the lungs, heart and kidneys.

Dexamethasone, a corticosteroid, decreases the immune response. This could be beneficial because it prevents an overwhelming response from the immune system but could also be harmful as it may prevent the immune system’s ability to contain the viral infection.

Studies of prior outbreaks of respiratory infections have suggested potential harm of corticosteroids. For instance, in a prospectivecohort study of 309 severely ill adults infected with the virus causing Middle East Respiratory Syndrome (MERS), people who received corticosteroids were less likely to clear the virus than people who did not (adjusted hazard ratio 0.35, 95% confidence interval 0.17 to 0.72), and there was no difference in the number of deaths.¹ In a meta-analysis of observational studies of people with influenza, those who received corticosteroids were more likely to die than those who did not (hazard ratio 1.75, 95% confidence interval 1.30-2.36).²

Conversely, in a randomized controlled trial of 277 patients with acute respiratory distress syndrome (ARDS) of different causes who received invasive mechanical ventilation at the time of randomization, the number of deaths at 60 days was reduced from 36.2% in the usual care group to 20.9% in the dexamethasone group (difference 15.3%, 95% confidence interval 4.9% to 25.9%).³ The trial was performed before the COVID-19 pandemic and therefore did not include patients with COVID-19.

On July 17, 2020, the RECOVERY trial was published.⁴ To date, this is the largest randomized trial on the effect of dexamethasone in hospitalized patients with COVID-19.

Questions

Does dexamethasone reduce the risk of death within 28 days after randomization in adults hospitalized for COVID-19?

Does dexamethasone reduce the need for invasive mechanical ventilation in adults hospitalized for COVID-19 who do not receive invasive mechanical ventilation?

Findings

The RECOVERY trial is a large randomized controlled trial conducted in the United Kingdom comparing a range of possible treatments. A total of 6,425 adults hospitalized for COVID-19 were enrolled: 2,104 participants were randomized in a 1:2 ratio to receive dexamethasone (6mg daily for up to 10 days) in addition to usual care, and 4,321 participants were randomized to receive usual care alone.

The effect of dexamethasone depended on the level of respiratory support that participants received at the time of randomization (p-value for trend <0.001).

In 1,007 participants who received invasive mechanical ventilation at the time of randomization, the risk of death at 28 days after randomization was reduced from 41.4% in the usual care group to 29.3% in the dexamethasone group (rate ratio 0.64, 95% confidence interval 0.51 to 0.81). The number-needed-to-treat to prevent 1 death was 9.

In participants who were not on invasive mechanical ventilation but required supplemental oxygen at the time of randomization, the risk of death at 28 days was reduced from 26.2% in the usual care group to 23.3% in the dexamethasone group (rate ratio 0.82, 95% confidence interval 0.72 to 0.94). The number-needed-to-treat to prevent 1 death was 35. In these participants, dexamethasone also reduced the need for mechanical ventilation, from 10.2% in the usual care group to 7.3% in the dexamethasone group (rate ratio 0.74, 95% confidence interval 0.59 to 0.92; Horby P, personal communication). The number-needed-to-treat to prevent 1 participant from receiving invasive mechanical ventilation was 35.

In 1,535 participants who did not receive supplemental oxygen at the time of randomization, dexamethasone tended to increase the risk of death at 28 days, from 14.0% in the usual care group to 17.8% in the dexamethasone group (rate ratio 1.19, 95% confidence interval 0.91 to 1.55).

Assuming that dexamethasone would be given to hospitalized patients with COVID-19 who require supplemental oxygen, but not to patients who do not require supplemental oxygen, and that the characteristics of patients with COVID-19 in hospitals in Ontario are similar to the characteristics of patients included in RECOVERY, we estimate that the appropriate implementation of dexamethasone into routine care of hospitalized patients with COVID-19 would reduce deaths in hospitalized patients in Ontario by 15% (95% confidence interval 4% to 24%) and the need for invasive mechanical ventilation by 24% (95% confidence interval 6% to 39%).

Interpretation

The large, well-performed RECOVERY trial provides strong, conclusive evidence that dexamethasone (6mg daily for up to 10 days) reduces the risk of death in hospitalized patients with COVID-19 who require supplemental oxygen and/or invasive mechanical ventilation.

Dexamethasone also reduces the need for future invasive mechanical ventilation in hospitalized patients with COVID-19 who are not on invasive mechanical ventilation but require supplemental oxygen.

In patients with COVID-19 who do not require supplemental oxygen or mechanical ventilation, dexamethasone is not effective and could even be harmful.

Although the RECOVERY trial was open to a pediatric population, the overwhelming majority of patients included in the trial were adults and results have yet to be reported for the subgroup of children.  Decisions on the use of dexamethasone in children would therefore need to be made on a case-by-case basis, taking into account illness severity and using pediatric equivalent doses.

Residents of long-term care homes with COVID-19 who were not hospitalized were not included in RECOVERY. Decisions on the use of dexamethasone in residents of long-term care homes who require supplemental oxygen would therefore need to be made on a case-by-case basis with attention to the potential for side effect, including increase in serum glucose levels (especially in patients with diabetes), fluid retention and neuropsychiatric adverse effects.

The results of RECOVERY should not be extrapolated to doses higher than 6mg of dexamethasone daily, to other corticosteroids, or to the treatment of patients without COVID-19.

Dexamethasone is widely available, inexpensive and straightforward to implement into routine care of patients with COVID-19 who require supplemental oxygen or mechanical ventilation in all hospitals in Ontario.

Methods Used for This Science Brief

We searched PubMed and Google Scholar. The search strategy used in PubMed, for example, involved the following combination of keywords: ((Dexamethasone[tiab] OR corticosteroid*[tiab]) AND covid*[tiab]). Then we searched the Cochrane COVID Review Bank, the COVID-19 Rapid Evidence Reviews, the Covid-19 TrialsTracker, the Joanna Briggs Institute’s COVID-19 Special Collection, LitCovid in PubMed, the National Collaborating Centre for Indigenous Health’s Updates on COVID-19, the Oxford COVID-19 Evidence Service, the World Health Organization’s Global Literature on Coronavirus Disease, and other COVID-19 specific resources listed by the Guidelines International Network and the McMaster Health Forum. In addition, we retrieved reports citing relevant articles through Google Scholar and reviewed references from identified articles for additional studies. The search was last updated on July 31, 2020.

To estimate the potential impact of an appropriate implementation of dexamethasone into routine care of hospitalized patients with COVID-19 in Ontario, we assumed that dexamethasone will be given to nearly all hospitalized patients with COVID-19 who require supplemental oxygen, but not to patients who do not require supplemental oxygen, and that the characteristics of patients with COVID-19 in hospitals in Ontario are similar to the characteristics of patients included in RECOVERY. We used a fixed-effect model to combine appropriate subgroup specific log rate ratios while appropriately taking into account statistical uncertainty of estimates. Then we expressed the pooled rate ratio from the fixed-effect model as a relative reduction in deaths in hospitalized patients in Ontario and a relative reduction in the need for invasive mechanical ventilation in percent (relative reduction = (1 – rate ratio) x 100), with corresponding 95% confidence intervals. A rate ratio of 0.80, for example, would correspond to a relative reduction of 20%.

1. 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. https://doi.org/10.1164/rccm.201706-1172OC
2. Ni Y-N, Chen G, Sun J, Liang B-M, Liang Z-A. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit Care Lond Engl. 2019;23(1):99. https://doi.org/10.1186/s13054-019-2395-8
3. 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. https://doi.org/10.1016/S2213-2600(19)30417-5
4. Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19 – preliminary report. N Engl J Med. Published online July 17, 2020. https://doi.org/10.1056/NEJMoa2021436

Author Contributions: PJ and AO wrote the first draft of the science brief. All authors contributed to the conception of the science brief, revised it critically for important intellectual content, and approved the final version.

Citation: Jüni P, Odutayo A, Allen U, et al. Dexamethasone in Patients Hospitalized for COVID-19. Science Briefs of the Ontario COVID-19 Science Advisory Table. 2020;1(1). https://doi.org/10.47326/ocsat.2020.01.01.1.0

Author Affiliations: The affiliations of the members of the Ontario COVID-19 Science Advisory Table can be found at www.covid19-sciencetable.ca.

Declarations of Interest: The declarations of interest of the members of the Ontario COVID-19 Science Advisory Table can be found at www.covid19-sciencetable.ca.

Copyright: 2020 Ontario COVID-19 Science Advisory Table. This is an open access document distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided that the original work is properly cited.

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