Today, Jeff is alive, one of millions of people who have recovered after being diagnosed with covid-19, the illness caused by the coronavirus. But if you ask his grateful family or even his doctors what kept him alive, the answer is unsettling.
“We don’t know, and they don’t really know either,” Marylu said.
Seven months into the pandemic, front-line doctors have in many cases become experts in treating covid-19. But they are experts without, for the most part, the most fundamental tool in medicine — solid evidence upon which to base their decisions.
When the coronavirus appeared in the United States in late January, hopes were high for quick progress: Science would find a treatment for people with the illness and develop a vaccine to prevent future cases.
Today, the vaccine race is on, but answers about treatments remain frustratingly elusive, with a handful of basic therapies supported by evidence, and a messy and imperfect scramble to extract information about what works from what has been given to thousands of patients. Therapeutic regimens vary from hospital to hospital, and much of what is offered is supported by hints and hunches — what official treatment guidelines refer to as a “knowledge gap.”
“There’s a lot of things about this pandemic that have been so challenging, and I just don’t think in the early days people really appreciated how important it was to set up rigorous clinical studies right away of treatments,” said Kevin Schulman, a professor of medicine at Stanford University School of Medicine. “We’re so focused on a vaccine, and hopefully they work. We’re a little less focused on drug trials and other treatments.”
Among other therapies, Jeff Seidel was given the anti-malarial drug hydroxychloroquine. It has since fallen out of vogue, in large part because of a big clinical trial in the United Kingdom that tested multiple drugs against placebos and found it did not work.
The National Institutes of Health is preparing to launch a large, randomized trial to formally test different doses of blood thinners, which have been widely used to treat blood clots caused by the virus. Blood plasma from people who have recovered has now been given to more than 60,000 covid-19 patients, but the evidence that it works is still only suggestive.
“It is unfortunate we don’t have the kinds of data we would like to have now,” said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. “That emphasizes and underscores something I repetitively talk about: the importance of the placebo-controlled randomized trial. Because if that had been done, we would have the answer to that right now … we could have [had] that answer some time ago.”
Medicine in a war zone
Rock-solid medical evidence depends on clinical trials, human experiments in which patients receive the real drug or a placebo. A flip of the coin determines whether patients get the real thing, and neither they nor their doctor know who is on the drug. These human experiments are essential, because even drugs backed by the most sensible rationale and promising lab research are often foiled by the trickiness of human biology.
But the uneven use of evidence to inform medical practice has long been a fissure running down the middle of American medicine — and that has turned into a chasm during the urgency of the pandemic.
“The U.S., for better and worse, is an every-person-for-himself kind of place,” said Christopher P. Austin, director of the National Center for Advancing Translational Sciences, part of the National Institutes of Health, the nation’s biomedical research agency. “ ‘Don’t tell me what to do, I’ve got the greatest idea in the world.’ Scientific discovery relies on that. But it is, in a situation like this, it is a counter-current.”
In normal times, doctors debate the art and science of medicine, argue for and against rigid guidelines and constantly navigate the gaps between peer-reviewed findings and their own years of experience. In a pandemic, when overwhelmed doctors scramble to treat patients, exhaust intensive care unit beds and are forced to reuse basic protective equipment, organizing the complex trials needed to rigorously test treatments has been even harder.
“It’s really a reflection of our general approach to clinical research,” said Robert Califf, a former commissioner of the Food and Drug Administration. “The pandemic has really exposed all the weaknesses that we already knew were there.”
Jeanne Marrazzo, an infectious diseases specialist at the University of Alabama at Birmingham, oversaw testing of remdesivir, an antiviral drug tested in a randomized trial that has since been authorized and is one of the research success stories of the pandemic. She says hand-wringing about the lack of gold-standard evidence simply does not take into account the situation on the ground.
“I think of what my clinical research team went through to enroll people in that trial, and I thought my nurses were going to die. One of them got covid and got sick,” Marrazzo said. In those early days, it took so long to get coronavirus test results that it could take a full day to get a patient qualified and screened for the study.
“Imagine trying to do that on a daily basis, multiple patients, some of them facing intubation, none of them have their families” with them, Marrazzo said.
Judith Aberg, chief of the division of infectious diseases at Mount Sinai Health System in New York who runs clinical trials, said she finds herself spanning an uneasy divide. Her health system set up randomized trials for some treatments, but not for others. That may have been a lost opportunity to gather precious data in the United States, but the chaos of delivering care in a pandemic made some medical ideals impossible.
“It’s not good science. But you’re talking about how many people died. There was one day our system had 84 deaths,” Aberg said. “And then you’re going to ask me to potentially put them on a placebo? It’s just really heart wrenching, talking with families, if your patients are able to communicate — and you’re dealing with all these deaths.”
But physicians’ decisions on how to use unproved treatments on dying patients reverberate: Doctors may never know why that individual patient recovered or got worse — but they also do not gain crucial knowledge about how to treat the next hundred, or thousand, patients.
“You can make an enormous contribution, if instead of just giving treatments, one was able to randomize. … Randomizing, versus just arbitrarily or willy-nilly giving out treatments, in hope that they might work, but no hope that you’ll ever know,” said Martin Landray, one of the leaders of the U.K. trial, called RECOVERY, that has enrolled more than 12,000 patients and provided practice-changing findings.
That trial has become the envy of many U.S. researchers, so far showing hydroxychloroquine does not work, a widely-used HIV combination drug also does not work and an inexpensive steroid called dexamethasone can save the lives of patients who require supplemental oxygen.
A treatment from medical history
The yellowish liquid transfused into Jeff Seidel’s body on April 12 has become emblematic of the divide over how to use medical evidence in a pandemic. The idea is simple: Blood plasma from recovered patients contains virus-fighting antibodies that, in theory, help other people thwart the virus. Though unproven against covid-19, such transfusions are supported by a clear medical rationale and a century-long history in medicine.
To those on the front lines, the effort to collect and give plasma during the pandemic is a rare success story, a grass-roots medical effort made possible by the volunteerism of donors. A small network of physicians came together to create a treatment option for patients and physicians with nothing else to offer, pushing against institutional and bureaucratic inertia.
Michael J. Joyner, a Mayo Clinic anesthesiologist who leads a program to provide expanded access to the plasma therapy that is sponsored by the FDA, said the first institutional approval he received was to treat 5,000 patients — and at the time, that seemed like a distant goal. Today, more than 64,000 people have received plasma, with no major safety issues. A promising new analysis, not yet peer-reviewed, found that people given plasma early were less likely to die than those who got it later and plasma with higher doses of antibodies appeared more beneficial, but could not prove the transfusion was the cause.
People such as Califf, the former FDA commissioner, point out that if only 1,000 of those people had been randomized into trials, we might know how it works. Instead, he and three other former commissioners wrote in The Washington Post, “we are not much closer to definitively answering those questions.” But Joyner warned against judging the pandemic with the benefit of hindsight.
“At the time, it was a widely accepted, efficacious therapeutic modality that got revivified at scale,” Joyner said. “The retrospectoscope is a wonderful tool in medicine, but please use a wide-angle retrospectoscope and wield it with full knowledge of what actually happened.”
Shmuel Shoham, an associate professor of medicine at Johns Hopkins University School of Medicine, is leading a randomized clinical trial of plasma for preventing disease in people who have had a high-risk exposure. He said the process of treating patients with the best available knowledge while also trying to collect data does not cause a conflict: It is more like wearing a belt and suspenders.
“Let’s do things that seem reasonable, and as more data is collected, we can learn lessons. It’s not traditionally the way medicine is done, but being in this hopefully once-in-a-lifetime situation has pushed us to do things that are different, and to take, with the acceptance of patients, risks we wouldn’t normally have taken,” Shoham said.
One of Jeff Seidel’s doctors in Wisconsin, anesthesiologist William Hartman, said that over time, his hospital system has learned to give plasma as early as possible — before patients are placed on ventilators. They learned this not by doing a randomized trial, but by collecting data on the people they treated and studying trends. Now, patients who are hospitalized are typically offered plasma right away.
Hartman acknowledged it is hard to separate out the effect of any one treatment because other factors could influence patients’ outcomes, such as the nursing care his hospital was able to deliver, because it was not overwhelmed by patients like many hospitals in New York.
“Not having a huge surge of patients, we can give very focused, one-on-one nursing care, attendants can be very involved,” Hartman said. “It’s a different level of care when there’s mass chaos, and … it is hard to weed that out.”
For individual patients, such discussions are abstractions. Marylu’s heart leaped when Jeff seemed to do better after receiving the plasma and he gave her the okay sign over FaceTime. It fell the next day, when he slid backward and the nurse said his prognosis was still a guessing game.
Months later, the Seidels are simply grateful to be back home. Jeff still gets winded but has been weaned from supplemental oxygen. He has spent the summer fishing and enjoying life again, able to hug his grandson.
Now, the Seidels are looking forward with trepidation once again. Doctors are only beginning to understand the long-term effects of the virus, and Jeff has a heart scan scheduled in October. When they hear people talk about how the virus is similar to the flu, they shake their heads.
“We lived it,” Marylu said. “It can affect you long-term. We worry about that, and we worry about what’s next.”