Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.
Ready or not, the patients were coming. This time last year, physicians around the world prepared, most for the first time in their careers, to treat a new disease—over and over and over again.
“There was a terrible sense of foreboding, like in a movie when the minor key music starts playing,” says Robert Arntfield, a critical care physician at Western University in London, Canada.
In Wuhan, China, the doctors who first encountered the pandemic coronavirus raced to share surprising symptoms and possible treatments with far-flung colleagues.
In Tokyo, ill cruise ship patrons from the Diamond Princess were wheeled into the hospital of the National Center for Global Health and Medicine. Infectious disease physician Norio Ohmagari dusted off the best treatment plan he had: one for the related coronavirus that causes Middle East respiratory syndrome. “Honestly,” he says, “we were not quite sure what we could do.”
In the United Kingdom’s Cynon Valley, a man arrived at a clinic for routine bloodwork, then announced he had a high fever and cough. Shouts went out for a doctor. As primary care physician Chris Butler prepared to assess the patient, “I was dropping my gloves,” he says. “I was pretty nervous.”
Over the harrowing year that followed, clinical evidence on how to treat the pandemic coronavirus poured in—a muddy torrent of hundreds of thousands of papers, preprints, and press releases. Many physicians were torn between waiting for results from large clinical trials, the gold standard of evidence, and offering something, anything, to the gravely ill patients in front of them. “These are smart physicians who are watching people get very sick, watching people die, feeling helpless, and wanting to do whatever they can,” says Lisa Moores, a pulmonary and critical care physician at the Uniformed Services University of the Health Sciences in Bethesda, Maryland.
Unproven drugs became first-line treatments. “Tens or hundreds of thousands of patients got ineffective or harmful therapies,” says Matthew Semler, a critical care physician at Vanderbilt University, citing widespread use of the antimalarial drug hydroxychloroquine, now known to prevent neither disease nor death.
Physicians memorized treatment guidelines one day only to learn they’d changed the next. “When you have the whole world working on something at the same time … the evidence evolves fast,” says Meghan Lane-Fall, a critical care physician who studies health care delivery at the University of Pennsylvania (UPenn). “Every time I take care of a COVID patient … I have to sit down and go, ‘OK, what are we doing now?’” Even today, she says, “There is no single standard of care.”
Yet 12 months after the World Health Organization (WHO) declared a pandemic, physicians have gleaned a rough understanding of COVID-19’s pathology and an aspirational strategy for treating it: Early in the illness, the goal is to stave off severe disease by stopping the virus from replicating. As infection progresses, the primary enemy becomes a hyperactive immune response that wreaks havoc on the body’s organs.
A few therapies—mostly repurposed drugs—have risen to the top. Dexamethasone, a cheap and common steroid, surprised doctors by slicing mortality in the sickest patients in a randomized trial; another anti-inflammatory, tocilizumab, also helped patients survive. The antiviral drug remdesivir, which appeared to speed recovery in some studies but not in others, is widely used in hospitalized patients. Monoclonal antibodies, meanwhile, are playing catch-up: Given early, they may help avert severe disease, but they can be tough to deliver to outpatients, and some appear less potent against new viral variants. Beyond drugs, physicians have honed their intensive care unit (ICU) practices to support patients’ failing organs.
COVID-19 remains enigmatic—and deadly—but shifts in care appear to have helped. An analysis published this month of nearly 200,000 patients in 555 U.S. hospitals found mortality rates dropped from 22.1% in March 2020 to 6.5% in August, although factors beyond new treatments, such as reduced crowding in hospitals, may have also played a role. After a traumatic year, doctors describe scientific progress they couldn’t have imagined—and a crisis that brought into stark relief the challenges of applying research to the art of medicine.
“I’m sorry to say that your COVID test came back positive.”
More than 120 million people have heard some version of those words, setting them on an uncertain path. About 10% to 15% will veer into serious illness, and others will face enduring, sometimes disabling symptoms. Gamely pumping the brakes are primary care doctors, trained to handle everything from warts to stomach bugs. “My patients are my family,” says Ada Stewart, a physician in South Carolina and president of the American Academy of Family Physicians (AAFP), who is haunted by the loss of about 10 of her patients to the virus.
Newly diagnosed patients “come into the clinic asking, ‘What can you give me right now that can prevent me from going down this pathway … [of becoming] very, very sick?’” says Jacqueline Chu, a physician in primary care and infectious disease who serves a working-class population in Chelsea, Massachusetts, that has been hit hard by COVID-19; her clinic is affiliated with nearby Massachusetts General Hospital.
Outpatient care is often basic, and Chu offers the same advice she does for riding out any virus at home: fluids, rest, and acetaminophen for pain and fever. But doctors now know which patients are more likely to develop serious disease; they keep closer tabs on the elderly and those with heart disease, diabetes, or obesity. When scientists at the Cleveland Clinic crunched data on everyone receiving a positive COVID-19 test through their health system, they identified another risk factor for severe illness: living in some of the poorest ZIP codes. Those patients now get 2 weeks of daily check-ins to spot symptoms quickly.
Doctors also know that even robust young people who appear to be recovering one day can deteriorate the next. To spot falling blood oxygen levels, pulse oximeters have become the new thermometers, widely recommended for home use.
Testing experimental treatments for newly diagnosed people has proved difficult. Some clinical trials struggle to find participants because community clinics are disconnected from trial infrastructure, says Butler, who runs the PRINCIPLE trial, among the largest studying high-risk people with COVID-19 at home, out of the University of Oxford’s Nuffield Department of Primary Care Health Sciences.
PRINCIPLE’s chief successes thus far have been in identifying what doesn’t work: In late January, it announced that the antibiotics azithromycin and doxycycline—tried because they have some anti-inflammatory and antiviral properties and because bacterial infections may set in after the virus takes hold—failed to speed recovery in outpatients.
Other trials have racked up failures, too. After months of urging COVID-19 survivors to donate antibody-rich plasma for infusion into infected people, the U.S. National Institutes of Health (NIH) this month halted a trial of convalescent plasma in patients with mild and moderate illness, finding it wasn’t improving outcomes. Last week, a preprint on a large U.K. trial reported no survival benefit in hospitalized patients, either. Trials in outpatients are ongoing.
Such failures can guide care and help doctors dissuade patients from embracing dubious treatments. “I had patients buying COVID ‘treatment packs’ from Mexico” that claimed to include antibiotics, steroids, and vitamins, says Andrew Carroll, a family physician in Chandler, Arizona. “None of this has any basis in research.”
Sarah Coles, who practices family medicine in nearby Phoenix, chairs the AAFP commission that issues treatment guidelines to its 136,000 members. These days she’s tracking data on a promising therapy: monoclonal antibodies. These labmade proteins mimic the body’s own immune response and are designed to block the virus from attaching to cells. In November 2020, after interim trial data suggested they could cut the risk of hospitalization by two-thirds and prevent deaths, the U.S. Food and Drug Administration (FDA) gave emergency use authorization to monoclonal antibodies made by the drug companies Regeneron and Eli Lilly and Co.
But the antibodies have to be infused at a hospital or specialized site within days of the first symptoms—a logistical challenge. “We have not created the on-ramps” to ease access, says David Wohl, an infectious disease doctor at the University of North Carolina (UNC), Chapel Hill, who’s working to widen the entry points. The 1800 doses administered at UNC are a fraction of what patients needed, he suspects. And in South Carolina, Stewart has rural patients without transportation for whom the therapy is literally out of reach. Meanwhile, supplies of the drugs have fluctuated, and at least some monoclonals seem to falter when facing new viral variants.
What’s more, official guidance is equivocal on antibodies. With clinical trials ongoing, NIH treatment guidelines say there are “currently insufficient data to recommend either for or against” most monoclonal antibodies, although on 2 March the agency suggested an Eli Lilly cocktail be offered to those at high risk of severe disease days after symptoms appear. The guidelines strike some physicians as too conservative. But Coles wants to see outcomes from more trial participants before fully embracing monoclonals. “We’ve been burned before,” she says.
With a meager arsenal, physicians like Coles and Stewart listen carefully, coach patients on symptoms to watch for, and make judgment calls. One day not long ago, a patient of Stewart’s 1 week out from diagnosis described intense fatigue and chest pain. Stewart felt her own worries rising. “Get to the hospital,” she advised. Once there, the patient turned out to have blood clots in both lungs and was quickly admitted—passing into the hands of a new medical team trying to shield her from the worst.
COVID-19 patients who arrive at the hospital doors have reached a precarious point. Most have endured at least a week of fever, coughing, and fatigue as viral particles multiplied throughout their bodies. Now, they’re on the cusp of a more perilous stage, in which a misfiring immune system can wreak havoc on their organs.
Elevated levels of immune signaling molecules in the blood are a marker of danger. But one of the clearest signs of trouble is a blood oxygen level below 94%, says Varidhi Nauriyal, an infectious disease specialist at the University of Pittsburgh. So the first treatment for people hospitalized with COVID-19 is oxygen, typically delivered through a mask or nasal prongs.
Most patients also get remdesivir, the lone COVID-19 treatment that’s been formally approved by FDA. The antiviral caught researchers’ attention early last year for its ability to inhibit SARS-CoV-2 in a lab dish. In April, an international NIH-sponsored trial reported that the drug shortened hospital stays by several days. But in October, WHO’s much larger trial, Solidarity, found no improvement in recovery time or mortality. NIH’s treatment guidelines recommend remdesivir, but WHO’s do not.
“It doesn’t seem to be the miracle drug that we would like it to be,” says Mangala Narasimhan, a pulmonary and critical care physician at New York’s Northwell Health system. But because remdesivir has few side effects and became entrenched in many treatment plans early in the pandemic, it remains standard therapy in most hospital wards and some ICUs, says Leora Horwitz, a hospitalist and health care systems researcher at New York University’s Langone Health. “I don’t think it’s going to do people any harm, I just don’t think it’s going to do them very much good,” she says.
Patients are also routinely treated for a common complication of COVID-19: blood clots, which develop in the veins of an estimated 17% of hospitalized patients and nearly 30% of ICU patients. Those clots can travel to the lungs, cutting off blood flow to the heart, or to the brain, where they can cause a stroke. Many guidelines call for giving most people a low, prophylactic dose of anticoagulants on admission.
But as patients worsen, physicians struggle over whether to up the anticoagulant dose, which boosts the risk of gastrointestinal and intracranial bleeding. Three trials—the United Kingdom’s REMAP-CAP, the NIH-led ACTIV-4, and Canada’s ATTACC—are rushing to clarify the risks and benefits.
In December 2020, all three trials stopped enrolling ICU patients, citing concerns about bleeding; preliminary results posted in a preprint this month found no survival benefit in the ICU. But in January, interim results from more than 1000 non-ICU patients looked promising: Compared with a prophylactic dose, full-dose blood thinners reduce the need for organ support and may also reduce mortality, NIH announced.
If those data hold up, they are “pretty profound,” says Todd Hecht, a hospitalist and director of the anticoagulation management program at the Hospital of the University of Pennsylvania (HUP). Perhaps ICU patients were simply so sick that high-dose anticoagulants had no effect, he says.
Large, randomized trials are the best way to disentangle the complex realities of COVID-19 care. But doctors sometimes sought faster ways to help the patients in front of them. At Henry Ford Hospital in Detroit, the flood of deteriorating patients in March 2020 prompted doctors to consider a then-unproven therapy: corticosteroids, drugs used for decades to reduce inflammation in conditions from asthma to allergies. Infectious disease specialist Mayur Ramesh and his team reviewed emerging evidence from China and decided to run what they called a “quasiexperiment.” Starting in late March, they gave all COVID-19 patients on oxygen a 3-day course of the corticosteroid methylprednisolone and compared their outcomes with those of patients admitted earlier.
The team debated doing a full clinical trial, says Nauriyal, who was then helping supervise Henry Ford’s ICU. But many had high hopes for the therapy and didn’t want to withhold it from a control group.
By early April, they saw a signal in their data: Of 81 patients admitted before steroids were added to treatment, 44% moved to the ICU and 26% died; for 132 patients admitted later, those numbers were 27% and 14%. Convinced the treatment was saving lives, Ramesh called colleagues at dozens of other institutions to spread the word. But without the rigor of a randomized trial or peer-reviewed data, few hospitals were willing to change their practice.
The Henry Ford team continued to dose patients with steroids, other medications, and oxygen, and many got better. But as everywhere, some patients deteriorated. As their lungs or other organs failed, they were transferred to a new space full of hissing and beeping equipment: the ICU.
“They’re all the same.” That was the impression Lane-Fall had when the first seven COVID-19 patients arrived in her ICU at HUP in March 2020. “And they’re all super-sick.”
U.S. records suggest nearly 30% of COVID-19 patients admitted to the hospital move to the ICU. Those critically ill patients face an inflammatory assault on their lungs and other organs. Many have multiple blood clots, and some require dialysis to support faltering kidneys.
When patients with lung failure began to fill ICUs 1 year ago, many physicians fell back on years of experience with acute respiratory distress syndrome (ARDS), a life-threatening buildup of fluid in lungs damaged by trauma or infection. “If someone had told me, ‘You’re going to be hearing a lot of stuff, but this is ARDS. Treat ARDS,’ that would have gone a huge way” toward reassuring physicians, says UPenn critical care physician George Anesi. In COVID-19 treatment, “Some of the foundational principles of critical care medicine really emerged [as] true,” he says. Those include proning—periodically flipping patients onto their stomachs to make full use of their lungs—and management of mechanical ventilators.
Choosing the right ventilator settings presents judgment calls. Forcing too much air into the lungs can further damage them. But delivering smaller, rationed breaths can distress patients; sedation to reduce that discomfort brings its own problems. Striking the right balance “is not drug development or anything fancy,” Semler says, “but this is what you’re actually doing all day, every day.”
An even bigger dilemma was who to put on ventilators in the first place. Because COVID-19 patients’ oxygen levels can crash abruptly, early wisdom was to insert a breathing tube at the first sign of trouble. Compared with noninvasive methods, mechanical ventilation was also suspected to better contain viral particles and carry less risk of infection for hospital staff. But patients who spend long periods on a ventilator generally face a long recovery. Gradually, physicians started to use ventilators more sparingly. A preprint released in mid-April suggesting less aggressive oxygen therapy did not increase airborne viral particles reassured some doctors about their own risk.
Instead of moving declining patients to a ventilator, some hospitals have tried a 6- to 24-hour “trial period” with a high-flow oxygen mask and careful monitoring, says critical care physician Massimiliano Greco of the Humanitas Research Hospital in Milan. “What we learned is that some of these patients can actually do well,” he says. Although a clinical trial might pinpoint the right time to intubate, Lane-Fall says the risks of intubating too early are already clear enough that a randomized trial wouldn’t be ethical.
But randomized trials have brought welcome clarity about one drug, the corticosteroid dexamethasone. Recovery, an Oxford-led effort with tens of thousands of hospitalized participants across the United Kingdom, included dexamethasone in trials of a lineup of potential therapies.
The results for the sickest patients were dramatic: In the subset of about 1000 Recovery participants on invasive mechanical ventilation, mortality 28 days after admission was 29%, versus 41% for those getting usual care. Given how many drugs fail in trials for critically ill patients, that effect size “was far in excess of anything that any grant reviewer would have said is even plausible,” says Kenneth Baillie, a critical care physician at the University of Edinburgh and one of the trial investigators. “I’m going to devote my whole career to medical research, and that one paper on steroids is probably going to be [my] most important.”
At Henry Ford, Ramesh’s team was ecstatic when Recovery announced results in June, a month after Ramesh and colleagues had published their methylprednisolone findings. Both drugs are steroids with similar methods of action, suggesting Henry Ford’s gamble hadn’t been far off base.
Yet for patients on oxygen but not ventilators, Recovery’s results were less dramatic: 23% mortality, versus 26% in patients who got usual care. Oxygen needs and severity of illness vary widely in that group, leaving some uncertainty about which patients benefited, notes UPenn critical care physician Nuala Meyer. That’s a cost of Recovery’s simple design, she says. The trial “needed to not be burdensome to providers,” she says, “but you sacrifice some level of detail.”
In Recovery participants who didn’t need supplemental oxygen at enrollment, dexamethasone was actually linked to increased mortality. That may be because early in disease, steroids can prevent the immune system from clearing the virus, Ramesh says. He worries that some emergency room and urgent care doctors are giving dexamethasone too soon. “If you don’t understand the timing, you are just throwing things at people,” he says. “You may be hurting them.”
Last month, another arm of the Recovery trial found mortality reductions with tocilizumab, a newer, more expensive anti-inflammatory drug approved to treat rheumatoid arthritis that blocks inflammatory signaling by the molecule interleukin-6. Those results echoed positive findings from the U.K. REMAP-CAP trial, first released in a January preprint.
Earlier trials had failed to find benefits. But most patients in the Recovery and REMAP-CAP trials were also getting dexamethasone, which may have tamed inflammation enough for tocilizumab to have an effect, says Roy Gulick, an infectious disease doctor at Weill Cornell Medicine who co-chairs the NIH COVID-19 treatment guidelines panel.
As with monoclonal antibodies, converting studies into treatment recommendations isn’t straightforward. With tocilizumab, “The big question from the data we have today is, which group benefits?” Gulick says. After weeks of deliberation, the NIH panel on 5 March recommended tocilizumab alongside dexamethasone for patients who resemble Recovery or REMAP-CAP participants in oxygen needs, inflammatory markers, and other factors.
Doctors may lack clarity about how best to use dexamethasone and tocilizumab, but having two proven drugs available against a brand-new virus is remarkable, says intensive care physician Antoine Vieillard-Baron of the Ambroise Paré University Hospital, outside of Paris. “It’s big, big news.”
One year into the pandemic, however, exhausted doctors long for much more: treatments that can stop patients from reaching the ICU, or even the hospital, in the first place. “The amount of death that we’ve seen this year is just terrible,” Narasimhan says. Vaccines are starting to curb infections in some parts of the world, but many people will get sick in the coming months. They need a treatment to stop viral replication before the inflammatory cascade begins.
“The real therapeutic approach would be a direct antiviral,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told Science earlier this year. Also needed are drugs that can silence the precise cellular signals driving inflammation, Baillie says. “How do we stop people dying of COVID?” he asks. “I think in the future, that must be achievable.”