Update (June 23): The RECOVERY group posted the results of its study on dexamethasone to medRxiv on June 22.
In a press release on Tuesday (June 16), researchers from a large, randomized controlled trial for COVID-19 treatments announced that they’d seen an improvement in survival at 28 days after entry into the trial for the sickest patients who received the drug dexamethasone. In ventilated patients in particular, giving the steroid reduced deaths by one-third in the RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial. And patients on supplemental oxygen who received dexamethasone had a 20 percent lower mortality rate than those who did not. In contrast, the press release reported no benefit of the medication in subjects who were not in need of respiratory support.
Although the results, which described the outcomes of 2,104 patients who received dexamethasone, are not yet published, their release has generated excitement. Already, hospitals in US states experiencing an increase in cases have changed their treatment guidelines to include dexamethasone, according to Reuters. Not only is the drug cheap and widely available, but the anti-inflammatory properties of the drug are a logical solution to the immune system overreaction that happens in severe COVID-19.
“It’s a very safe, generally well-tolerated—at reasonable doses—steroid that works predominantly by its anti-inflammatory effects,” says Matthew Cheng, a medical microbiologist and infectious disease physician at the McGill University Health Centre. “With regards to the press release, I was quite honestly elated. This is the first data that we have that suggests that a drug is able to improve the chances of survival in those that are critically ill, and so while I eagerly await the scientific publication I was absolutely thrilled to receive the news and to read about it yesterday,” he adds.
It makes sense that steroids should work. They help dampen the host response. They help knock down those inflammatory cytokines and all those white blood cells going to the lungs.—Bram Rochwerg, McMaster University
To be clear, the benefit of using dexamethasone is seen in the sickest hospitalized patients, says Bram Rochwerg, a critical care physician at McMaster University in Canada who was not involved in the RECOVERY trial. The drug should not be taken prophylactically or by stable outpatients with COVID-19, he adds.
“I think we were all astonished to see how effective it was,” the University of Oxford’s Richard Haynes, who is one of the leaders of the RECOVERY trial, writes in an email to The Scientist. “We tested it because we believed it could be effective, but I don’t think anyone was expecting to see quite such large effects.”
Dexamethasone is one of the glucocorticoids—a subgroup of steroid hormones also sometimes called corticosteroids—and the synthetic counterpart of the natural glucocorticoid cortisol. Cortisol, dexamethasone, and other similar molecules regulate the immune system by entering a cell’s nucleus and suppressing expression of genes that encode inflammatory cytokines and increasing expression of the gene that encodes Annexin A1, a protein that’s been shown to limit immune system overreactions.
Dexamethasone is a good glucocorticoid to use because it’s cheap—one of the cheapest drugs that is in hospitals—and very potent, says Jesús Villar, a critical care researcher at Dr. Negrín University Hospital in Spain who did not participate in the RECOVERY trial. And because the half-life of the drug is more than 36 hours, clinicians can give one intravenous dose a day, which simplifies treatment in the intensive care unit (ICU), he says.
These drugs “have been around for seventy, eighty years, and the utility of corticosteroids in all sorts of conditions comes and goes,” says Rochwerg. He adds that treatment with dexamethasone has proven useful in autoimmune diseases, and in the ICU it is often prescribed for sepsis and acute respiratory distress syndrome (ARDS).
ARDS is a syndrome with different causes, including pneumonia, sepsis, and inhalation injuries. Symptoms include shortness of breath, faster respiratory and heart rates, and dangerously low blood oxygen levels. According to Rochwerg, ARDS is inflammation-driven, so the problem is actually the intensity of the immune response, rather than the trigger itself. In ARDS, the body produces inflammatory cytokines, and white blood cells go into the alveoli of the lungs, potentially causing inflammation.
“COVID—in the extreme case—can cause ARDS, and that’s why people die predominantly,” Rochwerg says. People are sick for weeks upon weeks, by which time the virus might have cleared out of their systems, he explains, “but it’s their own bodies’ ramped-up inflammatory process that’s now caused all the damage in the lungs. Based on that idea, it makes sense that steroids should work. They help dampen the host response. They help knock down those inflammatory cytokines and all those white blood cells going to the lungs.”
In a randomized controlled trial conducted from 2013–2018 and published in February, clinicians and researchers in ICUs across Spain gave 139 ventilated patients with ARDS a once-daily intravenous dose of dexamethasone for five days, then cut the dose in half and gave it for another five days. For 138 control patients, doctors provided them the usual care for ARDS, which didn’t include dexamethasone. Subjects in the treatment group spent about five fewer days on a ventilator on average than the subjects that didn’t get dexamethasone. Mortality rates were also lower: 29 treated patients died by 60 days after the initiation of therapy, while 50 patients who did not receive dexamethasone died.
That trial was one of the first hints that dexamethasone might be beneficial in ARDS triggered by a viral infection—a question that’s been unresolved up to this point based on smaller studies and a 2019 meta analysis that indicated that corticosteroids put ARDS patients at greater risk of death. In the Spanish study, 62 patients—31 in each treatment arm—had ARDS caused by H1N1 influenza-related pneumonia. The number of deaths 60 days after randomization was lower in the group treated with dexamethasone, but due to the smaller sample size, the difference wasn’t statistically significant, Villar, who coauthored the study, tells The Scientist. The latest work in COVID-19 patients suggests to him that the findings in his study’s patients signaled a true response to the drug.
Tuesday “was a very happy day for our group,” he says. Villar and his colleagues started recruiting patients with COVID-19 for their own dexamethasone trial this spring, a process they’ve put on hold following the release of the preliminary RECOVERY results on Tuesday, out of concern for the ethics of not offering the drug to a control group, who might also benefit. Science reports that dexamethasone has already been given to many COVID-19 patients in Spanish ICUs. It will be important to see the formal publication from the RECOVERY team to determine which group of patients benefits the most, Villar adds.
On Tuesday in the UK, the chief medical officers of England, Wales, Scotland, and Northern Ireland wrote to all the doctors and hospitals to indicate that dexamethasone should become standard care for admitted patients with COVID-19 who require oxygen, Haynes tells The Scientist.
“I’m absolutely elated with the results at 28 days, but I am eagerly awaiting the longer-term follow up,” says Cheng. And dexamethasone “didn’t bring the mortality rate down to zero . . . so while the results are absolutely encouraging, we need to continue building upon them and potentially trying different combination strategies to further bring the mortality rates down. It should unequivocally be celebrated from the scientific community, but there’s still work to be done.”