Dexamethasone: A Marginally Beneficial Treatment for Severe COVID-19

At present, only a single drug has been demonstrated to reduce death rates in patients with serious coronavirus disease 2019 (COVID-19). That drug is dexamethasone (HEMADY), a highly potent synthetic corticosteroid (also called glucocorticoid) that has long been used to treat inflammatory illnesses and other serious conditions that can be detrimental to almost every organ system of the human body.

Overview of dexamethasone

Dexamethasone, which is available in both oral and injectable forms, suppresses the immune system and has strong anti-inflammatory properties. It is used to treat the following illnesses, among many others: shock accompanied by adrenal insufficiency (insufficient production of adrenal gland hormones); acute flare-ups of rheumatoid arthritis, osteoarthritis and multiple sclerosis; severe allergic skin reactions; severe asthma; severe inflammatory conditions of the eyes; ulcerative colitis (colon inflammation); leukemia; and cerebral edema (brain swelling) due to a variety of causes.[1]

Like all corticosteroids, dexamethasone can cause many adverse effects. The most common include adrenal suppression, high blood pressure, swelling, osteoporosis (decreased bone density leading to an increased risk of fractures), eye disorders (such as cataracts and glaucoma), heart disease, increased blood sugar levels (diabetes), infection, muscle weakness, psychiatric effects (such as agitation, anxiety, delusions, depression, hallucinations, insomnia, euphoria, mania and suicidal thoughts), slowed wound healing, skin fragility, ulcer in the stomach or duodenum, and weight gain.[2]

Despite concerns about toxicity and prior studies showing inconclusive (and sometimes harmful) results when corticosteroids were tested for treating other coronavirus infections,[3],[4] such drugs were widely considered to be a potential treatment for COVID-19 early in the pandemic. At least 55 clinical trials testing various corticosteroids for COVID-19 treatment have been initiated around the world.[5] Initial results from one such trial conducted in the United Kingdom prompted that nation’s chief medical officer and the U.S. National Institutes of Health to recommend the use of dexamethasone in certain hospitalized COVID-19 patients.[6],[7]

Randomized trials

To date, at least seven goodquality randomized trials have been conducted that jointly support the cautious use of corticosteroids as a treatment for certain patients with severe COVID-19.

The most influential randomized trial to date was published in the New England Journal of Medicine (NEJM), and it demonstrated that dexamethasone reduced deaths in a narrowly defined subset of patients hospitalized for COVID-19.[8] That trial randomized 2,104 hospitalized subjects to receive oral or intravenous dexamethasone and 4,321 to receive usual care. The subjects were divided into three groups based on illness severity when they entered the trial: 1) on invasive mechanical ventilation (324 dexamethasone and 683 usualcare subjects), 2) receiving supplemental oxygen without mechanical ventilation (1,279 and 2,604 subjects, respectively) and 3) breathing unassisted without supplemental oxygen (501 and 1,034 subjects, respectively).

Across all subjects, dexamethasone treatment yielded statistically significant reductions in 28-day follow-up death rates, but additional analyses showed that those significant reductions were only evident for the first two subgroups and that dexamethasone treatment actually may be harmful for those not receiving mechanical ventilation or oxygen.

Specifically, dexamethasone and usual-care death rates, respectively, were 29% and 41% for those on mechanical ventilation, 23% and 26% for the oxygen-only subgroup and 18% and 14% (opposite effect) for those not receiving oxygen. These results led to the conclusion that dexamethasone reduced COVID-19 deaths in hospitalized patients, but only in those requiring respiratory support.

A meta-analysis of clinical trials testing corticosteroid treatment for hospitalized COVID-19 patients was recently published in the Journal of the American Medical Association (JAMA).[9] It combined the results of seven well-designed randomized trials to estimate the impact of treating critically ill COVID-19 patients with one of the following three corticosteroids: dexamethasone (three trials), hydrocortisone (three trials) or methylprednisolone (one trial). The NEJM trial described above was the source of the majority (57%) of the subjects included in this meta-analysis. To focus on critically ill subjects, the JAMA study included only those 1,007 NEJM trial patients who were on mechanical ventilation. Accordingly, across the seven trials included in the meta-analysis, “critically ill” corresponded to patients requiring intubation, mechanical ventilation, intermediate or intensive care unit admission, or high-flow oxygen support.

Overall, the JAMA study involved 678 corticosteroid-treated and 1,025 usual-care or placebo-treated COVID-19 subjects spread across 10 nations. At 28 days of follow-up, 33% died in the steroid-treated group and 41% died in the usual-care or placebo group. This translated into a statistically significant absolute reduction in deaths related to steroid treatment of 8% (41% that died without corticosteroid treatment minus 33% that died with corticosteroid treatment).

What You Can Do

If you or a loved one are hospitalizedwith COVID-19 and require supplemental oxygen or mechanical ventilation, talk to your doctor about corticosteroid (especially dexamethasone) treatment, which could be lifesaving. Be aware that corticosteroids have many risks, need to be used at the right time and perhaps with other medications, and are far from a guaranteed remedy for severe COVID-19.
 

References

[1] Somerset Therapeutics. Label: dexamethasone sodium phosphate Injection. January 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5a1b0266-90c8-4176-a6b0-c4204d3c604e&type=display. Accessed September 30, 2020.

[2] Study suggests frequent improper use of systemic corticosteroids for respiratory illnesses. Worst Pills, Best Pills News. December 2018. /newsletters/view/1237. Accessed October 1, 2020.

[3] Cain DW, Cidlowski JA. After 62 years of regulating immunity, dexamethasone meets COVID-19. Nat Rev Immunol. 2020;20(10):587-588.

[4] RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 - Preliminary report. N Engl J Med. 2020 July 17;NEJMoa2021436. doi:10.1056/NEJMoa2021436. Online ahead of print.

[5] WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JA, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA. 2020 Sept 2. doi:10.1001/jama.2020.17023. Online ahead of print.

[6] Medicines & Healthcare products Regulatory Agency. Central alerting system: Dexamethasone in the treatment of COVID-19: Implementation and management of supply for treatment in hospitals. June 16, 2020. https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103054. Accessed October 1, 2020.

[7] National Institutes of Health. COVID-19 treatment guidelines: The National Institutes of Health COVID-19 Treatment Guidelines Panel provides recommendations for dexamethasone in patients with COVID-19. June 25, 2020. https://www.covid19treatmentguidelines.nih.gov/dexamethasone. Accessed October 1, 2020.

[8] RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 - Preliminary report. N Engl J Med. 2020 July 17;NEJMoa2021436. doi:10.1056/NEJMoa2021436. Online ahead of print.

[9] WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JA, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA. 2020 Sept 2. doi:10.1001/jama.2020.17023. Online ahead of print.