If most of us are confused about all the updates swirling COVID-19, imagine what it’s like for Adarsh Bhimraj. Not only has this Cleveland Clinic physician had to contend with a growing caseload, he’s part of a 16-person team in charge of managing the Infectious Diseases Society of America’s guidelines for treating COVID-19.
Between caring for patients at the Ohio hospital and even coming down with a mild case of coronavirus himself, Bhimraj has had to assess a steady stream of new information on how to treat the virus. Researchers around the world are conducting more than a thousand randomized clinical trials testing COVID-19 treatments. Bhimraj and his colleagues on the guidelines panel must navigate through this torrent and highlight the most promising results.
Uncertain though it still may be, knowledge of how the coronavirus works and how to fight it is slowly, surely accreting. Eight months into the pandemic, doctors are gaining a better handle on how to treat the disease. Some therapies are brand-new medications, while others are common medical staples previously shown in clinical trials to be safe and effective for different ailments. Other improvements have come from subtle changes to standard care. All of it, bit by bit, is saving lives.
“None of these therapies are, in Fauci’s words, ‘game-changers,’ right?” Bhimraj says, referencing statements made by Anthony Fauci, the director of the U.S. National Institute of Allergy and Infectious Diseases. “But they certainly show a signal that they could be helpful.”
Doctors interviewed by National Geographic emphasized that when it comes to treating COVID-19, no silver bullets or easy fixes have been discovered. Antiviral drugs, antibodies, and immune-boosting therapies, either administered by themselves or in multi-drug cocktails, will take time to refine. Even a vaccine won’t totally stop the virus in its tracks, and the long-term health burden of COVID-19 remains unknown.
“We, as yet, haven’t got the answers to all of this, and we’re going to be struggling with this across the world for the next year or two,” says University of Southampton immunopharmacologist Stephen Holgate. “Having a range of treatments available is going to be really important—and to have the clinical trial evidence that supports it, which is the crucial thing.”
Of the hundreds of research efforts seeking to validate COVID-19 remedies, one based at the University of Oxford appears to be the early standard-bearer when it comes to separating hope from hype. The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an extensive effort within the United Kingdom to test treatments for COVID-19.
One of the drugs among the array of possible treatments being tested is the steroid dexamethasone. COVID-19 can trigger an overzealous immune response, and like other steroids, dexamethasone can blunt and modify such a reaction. On June 16, the team published their early results about dexamethasone, which showed that among COVID-19 patients requiring oxygen or mechanical ventilation, dexamethasone cut the risk of death by a third, compared to standard therapy alone. For people with milder cases who don’t need oxygen support, dexamethasone doesn’t seem to help—and might even make things worse. But in the most severe cases, dexamethasone represents a potential lifeline.
“We announced results at lunchtime, and by teatime here, the chief medical officers here in the U.K. went to every hospital, saying they should adopt this as standard practice,” says Oxford cardiologist Martin Landray, a co-lead investigator on the RECOVERY trial. “And although I can't prove it, I think it's pretty certain that by the weekend, lives are being saved as a result of that.” The study was formally published in the New England Journal of Medicine on July 17.
Bhimraj praised the RECOVERY trial because of its ambition—and because its researchers followed their media announcement with full results. “I don’t mind the preprints; we’re having a hard time with the press releases,” he says, pointing to other instances when media announcements of promising treatments have gone months without follow-up.
How has RECOVERY arrived at clear answers, when other trials in the age of COVID-19 have faltered? Landray says that it’s become unwieldy to launch clinical trials, from lengthy and complicated consent forms to the cumbersome amount of data collected per patient. The RECOVERY trial, by contrast, was designed to be pragmatic—bare-bones, even—to recruit as many patients as possible. That’s valuable for a clinical trial because the larger the sample size, the likelier that researchers will see a verifiable signal of a treatment’s effectiveness. In partnership with the U.K.’s National Health Service, the RECOVERY trial successfully has recruited about 15,000 patients so far, which Landray says amounts to one in six of the U.K.’s hospitalized COVID-19 cases since the trial began.
On June 25, the Infectious Diseases Society of America updated its treatment guidelines to conditionally recommend dexamethasone, and the U.S. National Institutes of Health followed suit in its own guidelines. Though dexamethasone isn’t technically an FDA-approved medication for COVID-19 (no drug is), the steroid was the first medication shown to boost COVID-19 survival. Demand for the inexpensive drug—which costs about $25 per bottle—has risen so much, so quickly, U.S. pharmacists are reporting shortages.
The RECOVERY trial’s aim isn’t only to validate the winners, but also ascertain when a potential treatment is found wanting. In June, the researchers announced the results of a 4,716-person trial of hydroxychloroquine, the antimalarial drug championed by leaders such as U.S. President Donald Trump and Brazil President Jair Bolsonaro. The results—released without peer review on July 15—suggest that hydroxychloroquine offered no clear clinical benefit in treating COVID-19, a conclusion reached by a slate of other studies.
Despite clarifying the usefulness of a couple drugs, there are questions that the trial hasn’t yet answered. Landray says that he wants to test convalescent plasma, an antibody-rich transfusion made from the blood of recovered COVID-19 patients. In the U.S., blood plasma recently earned an emergency authorization on controversial grounds, but RECOVERY must wait for the fall to begin a trial, when cases—and recruits—might rise again during COVID-19’s anticipated winter wave.
One early advance in the broader hunt for treatments involved remdesivir, a repurposed antiviral that can slightly shorten COVID-19 recovery time. But researchers are also looking into ways to ramp up the body’s natural antiviral response. One potential avenue: interferon-beta, a protein involved in the human immune system.
Normally, when a cell is infected by a virus, it releases many versions of interferons that tell neighboring cells to switch on their germ defense and produce a cocktail of antiviral compounds. However, SARS-CoV-2 appears to be good at sneaking around these interferon tripwires. As a result, the initial response in the lungs doesn’t fully rev up, letting the virus run roughshod.
News of this pattern caught the attention of Synairgen, a U.K. biotechnology company. For years, Synairgen has been developing a breathable mist of interferon-beta to help severe asthma and chronic obstructive pulmonary disease patients better fight off viral infections.
In a July 20 presentation to investors, Synairgen representatives said that in a randomized trial with 101 hospitalized subjects, patients on interferon-beta were 79 percent less likely to die of the disease or require invasive ventilation than patients on standard care. Patients who received interferon-beta also recovered in greater numbers and reported less shortness of breath.
“To be frank, we were surprised at how effective this treatment was,” says University of Southampton’s Holgate, one of Synairgen’s co-founders. “You could understand that if this treatment was given at the very first stage of the disease, when the virus was taking occupancy in the lungs, you would have a good effect—but here we were, able to pull people back from going on a ventilator and accelerate their recovery.”
While the overall stats look promising, this early trial is small, so researchers can’t be sure yet whether the drug helps a lot, or only slightly. According to Holgate, Synairgen is recruiting in the U.K. for a larger, at-home clinical trial this fall. Other research suggests that using interferons to treat COVID-19 could depend on the timing: Give them too late, and they may do very little, or even risk harming late-stage patients by ramping up inflammation. This timing question is why Holgate was as surprised as he was with the initial trial’s positive results.
Whiz-bang pharmaceuticals aren’t the only source of hope in treating COVID-19. Just as important are basic preventions—masks, social distancing, hand washing—as well as improvements in standard care. The greater understanding doctors now have of the disease and support strategies almost certainly helped reduce U.S. deaths when COVID-19 spiked for a second time this summer.
“It’s true that having drugs like remdesivir and steroids is very helpful, [but] we don't want to forget about the importance of good medical care and critical care,” says Helen Boucher, the chief of geographic medicine and infectious diseases at Tufts Medical Center in Boston, Massachusetts. “It's even more important than ever that our health-care system can work.”
Take invasive ventilation. The procedure has saved many COVID-19 patients, but it’s not without risk: Pressure from ventilation can cause damage to the lungs, and the shock and discomfort of the situation—having a tube inserted down the windpipe, worrying about one’s survival—can cause symptoms of post-traumatic stress disorder. So researchers have been looking at ways to limit the damage and distress of intubation and use less invasive methods to improve patients’ breathing and blood oxygen levels.
“A common mistake is to get excited and be chasing things that may seem esoteric, and to abandon the things we know work well,” says Christian Bime, a researcher and ICU medical director at the University of Arizona. “Good old-fashioned public health may seem boring, but it works!”
The old-school playbook comes from a well-studied injury called acute respiratory distress syndrome (ARDS), which has symptoms that mirror the lung damage seen in severe COVID-19. For instance, Bime and his colleagues have had success with an ARDS technique called lung-protective ventilation: tweaking a mechanical ventilator’s settings to limit the pressure and volume of the air blown into the lungs, preventing strain that could cause further duress.
Bime points to the surprising success of another straightforward technique: laying COVID-19 patients on their stomachs. “That’s one of the things we’ve found very, very helpful in COVID patients across the board,” he says.
Lying stomach-down—also known as prone positioning—improves the lungs’ ability to get oxygen into the blood. The heart sits in the front of the chest, so flipping someone onto their stomach takes the weight of the heart off of the lungs. The back of the lungs also have better blood flow and more gas-exchange chambers than the front, which means that when someone’s lying stomach-down, these chambers are less compressed and work more effectively.
“You want blood flow and gas exchange to line up nicely, and putting someone in the prone position maximizes that effect,” says Kevin McGurk, a chief emergency medicine resident at Cook County Health in Chicago, Illinois.
Logistically speaking, prone positioning isn’t always easy. Safely rotating a patient hooked up to IVs and a mechanical ventilator can take five people to perform. Multiply that routine by dozens or hundreds of patients, and it can stress an already stretched-thin medical staff. But in several case studies and reviews from around the world, including one co-authored by McGurk, physicians report that in combination with supplemental oxygen, prone positioning also can improve blood oxygen in awake COVID-19 patients with milder symptoms. It may even lower the risk of someone needing invasive ventilation.
“This is not a magic cure, but ... it's actually been fairly remarkable how many people respond to prone positioning, and often pretty rapidly,” McGurk adds. “There's not a lot of downside to asking someone who's awake to try lying on their belly.”