Back >>

Is there any literature on dexamethasone for COVID-19?

Comment by InpharmD Researcher

The use of corticosteroids (including dexamethasone) in COVID-19 is controversial. New evidence (RECOVERY trial) suggests there may be a mortality benefit of dexamethasone 6 mg (either IV or PO) once daily for up to 10 days in severe, ventilated patients when started around 8-9 days after symptom onset [Table 1]. However, older evidence suggests no net benefit with systemic corticosteroid use in coronavirus diseases with an increased risk of adverse events and delayed viral clearance.
Background

Per the most updated (May 27, 2020) World Health Organization (WHO) guidelines for COVID-19, corticosteroid use in COVID-19 patients may be considered in exacerbation of asthma or chronic obstructive pulmonary disease (COPD), septic shock or ARDS, and based off of risk/benefit analysis for individual patients. In general, the recommends against the routine use of systemic corticosteroids for viral pneumonia. Systematic reviews and meta-analysis of coronavirus diseases (SARS-CoV-2, SARS-CoV and MERS-CoV) found that corticosteroids did not significantly reduce the risk of death, did not reduce hospitalization duration, and/or use of mechanical ventilation, and had several adverse effects. Avascular necrosis, psychosis, diabetes, delayed viral clearance, and secondary infections may hinder the use of corticosteroids. [1]

Per the National Institute of Health guidelines, systemic corticosteroids can affect the pathogenesis of viral infections in various ways. In outbreaks of other novel coronavirus infections (i.e., Middle East respiratory syndrome [MERS] and severe acute respiratory syndrome [SARS]), corticosteroid therapy was associated with delayed virus clearance. In severe pneumonia caused by influenza, corticosteroid therapy may worsen clinical outcomes, including secondary bacterial infection and mortality. Conversely, the potent anti-inflammatory effects of corticosteroids are proposed to have a potential therapeutic role in suppressing cytokine-related lung injury. Data on the use of corticosteroids in COVID-19 are limited. The recommendations for the use of corticosteroids in patients with COVID-19 depend on the severity of illness, indication, and underlying medical conditions and should be considered on a case-by-case basis. [2]

Surviving Sepsis Campaign guidelines on the management of critically ill adults with COVID-19 recommend against the use of systemic corticosteroids in mechanically ventilated adults with COVID-19 and respiratory failure (without ARDS). However, in patients who are mechanically ventilated adults with COVID-19 AND have ARDS, the use of systemic corticosteroids is recommended. This is due to weak evidence suggesting methylprednisolone at 1–2 mg/kg/day for 5–7 days was associated with shorter duration of supplemental oxygen use. [3]

Preliminary results of a randomized, controlled trial (RECOVERY) comparing dexamethasone to “usual care” were reported to have a mortality benefit in patients who were critically ill and on ventilators [Table 1]. This same benefit was not seen in patients who were on oxygen therapy alone. Steroid use in COVID-19 has been controversial due to data from Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) being ambiguous. This new data showed dexamethasone 6 mg (either PO or IV) showed a mortality benefit when started around 8-9 days of symptom onset. [4]

An editorial suggests that dexamethasone may be used short term in severe COVID-19, intubated patients, but could also be dangerous during recovery due to persistence of virus and lack of protective antibodies. Intravenous dexamethasone pulse may be given followed by nebulized triamcinolone to concentrate in the lung only. Both could also be given together with natural flavonoid luteolin because of its antiviral, anti-inflammatory, mast cells inhibition properties. This has the potential to be useful against pro-inflammatory cytokine storms, which is associated with high morbidity and mortality in patients with COVID-19. However, steroid use also inhibits the protective function of T and B cells, potentially leading to increased plasma viral load after the patient survives COVID-19. Patients may also be at a risk of secondary, nosocomial infection with steroid use. [5]

An upcoming randomized, controlled trial studied dexamethasone in combination with intravenous immunoglobulin (IVIG) and interferon-beta in critically ill patients with COVID-19. The results of this study have not been published yet, but the last patients have been enrolled. [6]

References:

[1] World Health Organization. Clinical Management of COVID-19. https://www.who.int/publications/i/item/clinical-management-of-covid-19. Published May 27, 2019. Accessed June 23, 2020.
[2] National Institute of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf. Published June 16, 2020. Accessed June 23, 2020.
[3] Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-887.
[4] Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives. Nature. 2020;582:469.
[5] Theoharides TC, Conti P. Dexamethasone for COVID-19? Not so fast. J Biol Regul Homeost Agents. 2020;34(3):[E-pub].
[6] Abdolahi N, Kaheh E, Golsha R, et al. Letter to the editor: efficacy of different methods of combination regimen administrations including dexamethasone, intravenous immunoglobulin, and interferon-beta to treat critically ill COVID-19 patients: a structured summary of a study protocol for a randomized controlled trial. Trials. 2020;21(1):549. Published 2020 Jun 19. doi:10.1186/s13063-020-04499-5

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is there any literature on dexamethasone for COVID-19?

Please see Table 1 for your response.


 

Effect of Dexamethasone in hospitalized patients with COVID-19 - Preliminary report 

Design

Randomized, controlled, open-label, adaptive, platform trial

N = 6,425

Objective

To evaluate the effects of potential treatments in patients hospitalized with COVID-19

Study Groups

Dexamethasone (n=2,104)

Usual care (n=4,321)

Methods

Inclusion criteria: clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trail

Exclusion criteria: dexamethasone considered either indicated or contraindicated, dexamethasone unavailable at the hospital at time of enrollment

Eligible patients were assigned 2:1 to either usual standard of care or usual standard of care plus dexamethasone 6 mg (either PO or IV) once daily for up to 10 days (or discharge, if sooner). Patients could also be randomized to other treatment arms, but the results are not presented with this manuscript.

Duration

Follow-up: 28 days

Outcome Measures

Primary outcome: all-cause mortality within 28 days of randomization

Secondary outcomes: time to discharge from hospital (within 28 days), subsequent receipt of invasive mechanical ventilation (including extra-corporeal membrane oxygenation) or death (among patients not receiving invasive mechanical ventilation at randomization)

Baseline Characteristics

 

Dexamethasone (n=2,104)

Usual care (n=4,321)

 

Age, years

66.9 ± 15.4 65.8 ± 15.8

Women

766 (36%) 1,571 (36%)

Days since symptom onset (IQR)

8 (5-13) 9 (5-13)

Respiratory support received

No oxygen

Oxygen only

Invasive mechanical ventilation

 

501 (24%)

1,279 (61%)

324 (15%)

 

1,034 (24%)

2,604 (60%)

683 (16%)

IQR=inter-quartile range

Results

 

Dexamethasone (n=2,104)

Usual care (n=4,321)

RR (95% CI)

P-value

28-day mortality

No oxygen

Oxygen only

Invasive mechanical ventilation

454 (21.6%)

85/501 (17%)

275/1,279 (21.5%)

94/324 (29%)

1,065 (24.6%)

137/1,034 (13.2%)

650/2,064 (25%)

278/683 (40.7%)

0.83 (0.74-0.92) 

1.22 (0.93-1.61)

0.80 (0.70-0.92)

0.65 (0.51-0.82)

<0.001

0.14

0.002

<0.001

Discharge from hospital within 28 days

1,360 (64.6%)

2,639 (61.1%)

1.11 (1.04-1.19)

0.002

Receipt of invasive mechanical ventilation*

92/1,780 (5.2%)

258/3,638 (7.1%)

0.76 (0.61-0.96) 0.021
Death* 360/1,780 (20.2%) 787/3,638 (21.6%) 0.91 (0.82-1.01) 0.07

RR=rate ratio; CI=confidence interval

*excluded those on invasive mechanical ventilation at randomization

Of those allocated to dexamethasone, 95% received at least one dose and they were treated for a median of 6 days. This is in contrast to 7% of the usual care group who received at least one dose of dexamethasone.

Adverse Events

Not reported

Study Author Conclusions

In hospitalized patients with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen, but not among patients not receiving respiratory support.

InpharmD Researcher Critique

This trial provides evidence that dexamethasone 6 mg once daily for up to 10 days reduced 28-day mortality among patients receiving respiratory support. Patients not receiving respiratory support saw no benefit (and the possibility of harm).

Approximately 7% of the patients were crossed over, as some of the usual care also involved dexamethasone. This was also an open-label study in a relatively sick population. Furthermore, this data is presented as preliminary results of an unpublished, non-peer-reviewed pre-print.



References:

Horby, P, Lim WS, Emberson J, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv 2020.06.22.20137273; doi: 10.1101/2020.06.22.20137273