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One year into the COVID-19 pandemic, hospital physicians say the best and most reliable drug for the illness is cheap, familiar, and has all the glamour of a Bayer aspirin.

It's dexamethasone, the steroid workhorse that's been around longer than most of the doctors who prescribe it.

"I love the irony that one of the cheapest medications that exists is one of the only ones that has shown any benefit," said University of California San Francisco hospitalist Charlie Wray, DO, in an interview. "We know the side effect profiles, we know the risks, and we know that the benefit could be saving a life."

Physicians say dexamethasone shows more benefit than drugs that have made a splash in the media such as remdesivir and convalescent plasma. But warn about dexamethasone's infamous side effects, which can be especially common in the older patients most prone to severe cases of COVID-19, and they urge caution about its use in patients who don't yet need oxygen.

Corticosteroids weren't always the hot drug for COVID. In the early days of the pandemic, "there was a big outpouring of because there was literature from SARS and MERS that found patients who got steroids had higher viral loads," recalled critical care pharmacist Michael Sirimaturos, PharmD, of Houston Methodist Hospital. "In those coronavirus disorders, the steroids seemed to make the virus replicate more or delay the immune system's response to clear it."

His hospital followed the steroid guidance when it saw its first case on March 13, Sirimaturos said. "But then we started getting more and more patients and realizing they weren't getting any better. They were in the hospital for 2-3 weeks, and they started showing classic signs of acute respiratory distress syndrome."

Steroids had previously shown value in treatment for ARDS, he said, while other drugs like hydroxychloroquine weren't working, and the patients "looked terrible and weren't getting better." So the hospital changed course and started administering steroids and saw a significant impact: "Wow, the patients are doing better, the chest x-rays are looking better, their oxygen saturations are getting better."

An in July supported use of dexamethasone. It found that 28-day mortality was reduced among patients on oxygen alone (23.3% vs 26.2% with standard care; RR 0.82; 95% CI 0.72-0.94) or a mechanical ventilator (29.3% vs 41.4%; RR 0.64; 95% CI 0.51-0.81).

On the other hand, death rates were higher when the drug was given before oxygen supplementation relative to standard care (17.8% vs 14.0%; RR 1.19; 95% CI 0.91-1.55).

"If you look at the treatments we have for COVID -- remdesivir, convalescent plasma, dexamethasone -- the only one shown to have a mortality benefit is dexamethasone" said Wray, the San Francisco hospitalist. "Convalescent plasma doesn't really work. Remdesivir shortens hospital length of stay, which is a nice thing to do," but doesn't affect mortality.

Research released in September found that other steroids, too, are beneficial in COVID. The about steroids and COVID notes that "if dexamethasone is not available, alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone can be used."

Dexamethasone has been around for more than 60 years. Unlike other COVID treatments, it is inexpensive, although its in recent months, with one analyst calling this worrisome while also noting that the price is historically volatile.

There have been shortages of specific doses of dexamethasone but they haven't been significant enough to affect its overall availability, said Michael Ganio, PharmD, senior director of Pharmacy Practice and Quality at the American Society of Hospital Pharmacists, in an interview. "The shortages shouldn't be impacting care, although they may make operations difficult if you only have access to the larger amounts or you have to draw up a dose from multiple vials."

It can be tricky to figure out when to start and stop dexamethasone or other steroids in COVID. If you start them too early, they'll dampen the immune system when it needs to be strong, pharmacist Sirimaturos said. Start them too late and you may miss the period when the body is overreacting and causing havoc in the lungs.

But physicians agree that the drug is helpful and in general should be given when patients are on supplemental oxygen or earlier in some cases. "If you've got a very sick individual in front of you, you should have a low threshold to start steroids if the patient is deteriorating," Wray said. "If you're ever in doubt, I would give steroids."

New Orleans pulmonologist Joshua Denson, MD, agreed. "Outside of the context of [supplemental] oxygen, I'd be trying to find another indication to support giving them," he said in an interview. Even then, "you'd have to have a pretty strong justification."

Some patients with underlying disorders such as asthma and COPD may already be on steroids before they need oxygen therapy, and they should get their doses increased, Denson said. But Sirimaturos, the pharmacist, cautioned that COVID can trigger reactivation of herpes simplex virus and cytomegalovirus, and steroids must be used carefully in patients with those disorders.

At the University of Minnesota, the protocol is to start dexamethasone in COVID-positive patients who are hypoxic (<90% on room air) and stop it when the patient is no longer hypoxic or at discharge, said hospitalist Benji Mathews, MD. "Continuing dexamethasone in COVID-19 patients who are not hypoxic increases their risk," he said.

The dexamethasone "should be continued for up to 10 days or until hospital discharge, whichever comes first."

Sirimaturos agreed that it's important to not keep patients on steroids indefinitely. "You should see a benefit within the first 3-4 days. Maybe reevaluate 4-5 days in. Just because steroids are good doesn't mean they should be on them forever. I do see that physicians like to keep patients on them longer than necessary."

Dexamethasone is , as the nation learned when President Trump insisted on taking a limousine ride after getting it during his bout with COVID. "Steroid-induced psychosis or altered mental status is quite common, especially in older adults," said New Orleans pulmonologist Denson. "If it occurs, you can try reducing the dose and making their daily routine as similar to normal as possible – awake in daytime and asleep at nighttime. You can try other medications as needed as that might help."

Wray advised colleagues to "be aware that steroid-induced psychosis can look a lot like hospital delirium, an extremely common entity we see in patients who are hospitalized and are very sick -- where people become hyperactive, unable to sleep, and with altered mental status. Teasing these two phenomena out from one another can be difficult."

In either case, he said, "we do our best to reorient the patient to where they are and what's going on. If possible, we like to have family at bedside to help reorient them, as well. But that's not really possible right now. Finally, we do small things like giving steroids in the morning so that they don't interfere with sleep patterns too much."

What's next? Multiple studies are to examine steroids as treatments for COVID. , which is expected to be completed this month, examines whether treatment with prednisone will help patients with mild disease avoid exacerbation.

For now, "steroids are the best thing we have," pulmonologist Denson said, "and that's pretty weak sauce."

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