However, one relatively common and inexpensive drug has emerged with the strongest evidence yet of improving Covid-19 survival and mortality in severely ill patients.
In the RECOVERY Trial, a randomized controlled trial led by the University of Oxford, scientists discovered that the steroid dexamethasone can bring severely ill patients back from the brink of death. The team announced their results on June 16.
In the trial, dexamethasone reduced the deaths of one in three Covid-19 patients on mechanical ventilators. It also reduced the deaths of one in five Covid-19 patients receiving oxygen without mechanical ventilation. For patients who did not receive these interventions, the drug did not influence mortality.
The recent pre-print report — which has not completed peer review — is changing how health professionals treat patients sickest with Covid-19.
“Unlike many other experimental therapies, when dexamethasone is used at the right time, for the right patient, there is a significant improvement in survival,” Mark Slifka, a microbiologist who studies immunity and vaccine development at Oregon Health and Science University, tells Inverse. Slifka was not involved in the RECOVERY Trial.
Craig Coopersmith, a surgeon and director of Emory’s Critical Care Center, says the findings are "quite significant" especially in the intensive care unit setting. Coopersmith was not involved in the trial.
"We currently have no treatments that decrease mortality in Covid-19," Coopersmith tells Inverse. "This is the first large study to show that an intervention improves survival."
When fighting Covid-19, some patients experience such serious lung damage and respiratory distress that they need ventilators or to receive high-pressure oxygen. The preliminary data, derived from over 6,000 Covid-19 patients, suggests dexamethasone could help this category of severely ill Covid-19 patients avoid "falling off a cliff" and survive the brutal disease.
"In the sickest patients with Covid-19, it appears that dexamethasone has the potential to save numerous lives," Coopersmith says. "While these results are very exciting, we eagerly await the final results from the study after they have undergone peer review and are published afterward."
The RECOVERY Trial compared various experimental therapies with usual care for Covid-19. About 15 percent of all hospitalized patients with Covid-19 in the United Kingdom were enrolled in the trial.
The team reports what happened to hospitalized Covid-19 patients when they were given six milligrams of dexamethasone once daily for up to 10 days, versus usual care or no additional experimental treatment. They examined whether these patients lived or died over a 28 day period.
Approximately 2,104 patients were randomly allocated dexamethasone, while 4,321 patients were allocated usual care. Over the study period, 21.6 percent of patients allocated dexamethasone and 24.6 percent of patients allocated usual care died.
"Dexamethasone has the potential to save numerous lives."
Dexamethasone reduced deaths by one-third — 29 percent — in patients on mechanical ventilators. For patients receiving oxygen but who were not on ventilators, dexamethasone reduced mortality by one-fifth or 21.5 percent. On average, these patients received one daily dose of dexamethasone for 6 days. Taking dexamethasone was associated with hospital stays one day shorter than usual care.
Based on these results, 1 in 8 patients on ventilators could be saved by the dexamethasone. In turn, 1 in 25 patients who require oxygen but no ventilator could be also saved.
Dexamethasone isn’t for everyone — the drug did not reduce mortality in patients not receiving respiratory support. This result suggests dexamethasone is crucial for patients in the late stages of fighting Covid-19.
How does dexamethasone help fight Covid-19?
When a person encounters a virus like SARS-CoV-2 the immune system activates, ramping up inflammation and producing virus-fighting white blood cells. Inflammatory responses during early, mild infection can help clear the infection, Slifka explains.
"If the infection is prolonged, or virus levels begin to exceed what the human host can handle, then inflammation and harmful cytokines can wreak havoc," Slifka says.
Sometimes, the immune system spirals into overdrive, creating an outsized inflammatory response called a cytokine storm.
Cytokine storms have been linked with Covid-19 patients’ sudden crash, marking the rapid transition from mild Covid-19 to severe disease.
"This is why dexamethasone is not used early in the course of infection when you want to generate immune responses but is an important tool to use later in the course of infection if the host immune responses begin to do more harm than good," Slifka says.
Scientists think that dexamethasone, an anti-inflammatory corticosteroid, helps slow down immune system activity, minimize inflammation, and suppress these cytokine storms. It doesn't change who catches Covid-19. It does, seemingly, help a subset of patients who are likely to die, live.
"Steroids suppress the immune system so it is likely that dexamethasone is playing a role through depressing immunity," Coopersmith explains. "The specifics of how it alters inflammation, which cell type, which mediators, which organs are entirely unknown. While one can speculate, it would be just that – speculation."
Importantly, timing and dose matter. The researchers write that "high doses may be more harmful than helpful" and that it should be given "at a time when control of viral replication is paramount and inflammation is minimal."
Coopersmith notes that dexamethasone does not appear to be helpful, and could even be harmful to, asymptomatic patients or patients with mild cases.
"This work is significant because it clears up the confusion and shows this treatment is effective if used at the right time during the course of disease."
Corticosteroids like dexamethasone have been widely used in syndromes closely related to Covid-19 like SARS, MERS, severe influenza, and community-acquired pneumonia, the researchers write.
However, up until this report, there has been been "considerable confusion" over the role of steroid use for Covid-19, Slifka says. Prior to the completion of this trial, many treatment guidelines have stated that corticosteroids are either "contraindicated" or "not recommended" in treating Covid-19.
"This work is significant because it clears up the confusion and shows this treatment is effective if used at the right time during the course of disease," Slifka says.
These preliminary results are already being put into practice in the United Kingdom: The first results were reported on June 16, 2020, just 98 days after the trial was first designed, and were adopted into practice later the same day.
Who makes dexamethasone?
The steroid is cheap and is considered as widely available. In a hospital setting, it can be used for $6 a day. Because patients are treated for an average of seven to 10 days, experts anticipate treatment for Covid-19 would cost $44.
The future of dexamethasone — Coopersmith is involved in writing national Covid-19 guidelines for the United States and says new guidance on this drug will be released very soon.
"[Before that is released] many practitioners will immediately start using dexamethasone on their severe Covid-19 patients, especially those in the ICU," Coopersmith says. "Some may choose to wait until the manuscript undergoes peer review since the data has not been vetted by outside reviewers yet."
Dexamethasone is off-patent, relatively cheap, and accessible, but if every patient with Covid-19 who enters the hospital and is placed on oxygen or the ventilator subsequently goes on dexamethasone, there is the potential for a shortage, Coopersmith says.
Since the trial findings came out, there has been “a degree of irrational exuberance,” about dexamethasone, Stephen Schondelmeyer, director of the Pharmaceutical Research in Management and Economics Institute at the University of Minnesota, Twin Cities, told Science. “We are already seeing hoarding behaviors and lack of availability of the product because of it."
Ultimately, the report needs to complete peer review before it can be supported with absolute certainty. But the results are striking — and experts are eager to see what happens next.