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Notebook Medicine

Nati Harnik/AP

Dexamethasone (Nati Harnik/AP)


Success with a steroid

Finally, a cheap, effective, and uncontroversial COVID-19 treatment

In March, a study in Wuhan, China, suggested that coronavirus patients might benefit from a potent steroid called methylprednisolone. But the study’s preliminary nature and its small number of participants limited its impact: At the time, the Eastern Virginia Medical School guidelines, which have helped guide COVID-19 treatment elsewhere, warned that “this topic is controversial” before summarizing the Wuhan findings and suggesting steroids may help.

Now, those findings have received support from the Recovery study, a University of Oxford clinical trial enrolling over 11,500 patients so far at 175 hospitals in the U.K. Recovery is investigating five potential treatments for COVID-19. One arm of the study, with over 2,100 patients, is investigating the steroid dexamethasone. (With hydroxychloroquine eliminated on June 5, the remaining candidates in the study are the anti-HIV combination drug Kaletra, the antibiotic azithromycin, plasma from recovered patients, and an anti-inflammatory called tocilizumab.)

The chief investigators write:

Dexamethasone reduced deaths by one-third in ventilated patients … and by one-fifth in other patients receiving oxygen only. ... There was no benefit among those patients who did not require respiratory support.

Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.

This is excellent news, for several reasons. The first is obvious: A drug has now demonstrated clinical benefit for COVID-19 patients in a large, well-run trial. The second reason is less obvious but equally significant: Dexamethasone is cheap, easily manufactured, and generally well tolerated in short courses. It lacks the harsh side effects of hydroxychloroquine. Unlike remdesivir, its supply is so plentiful that it is routinely given to prevent nausea in surgical patients. Nor are pharmaceutical patents an issue—dexamethasone has been in clinical use for about 60 years, so generic manufacturers worldwide can produce it.

Every answer in research raises more questions. Steroids are not a single drug but an entire class of them (dexamethasone belongs to the group called glucocorticoids, distinct from anabolic steroids, the drugs weightlifters occasionally abuse to bulk up). Which steroid is best? How much should patients receive, and how often? Should other drugs accompany it, to enhance its effect or to mitigate side effects? How will diabetics, who are prone to severe COVID-19 but whose blood sugar often rises significantly with steroid therapy, fare?

Another logical question is how we should respond, in terms of treatments and preventive efforts. This one is simpler: Outside of the hospital, little needs to change, because dexamethasone does not prevent coronavirus infection. Nor does the drug help minor COVID-19 cases, since it appears to work by tapping the brakes on the “cytokine storm” of an overactive immune system response to the virus. Because of this, patients only benefit from it once their condition is serious enough that they’re in the hospital, receiving oxygen or on a ventilator. (Patients in the Recovery trial showed no benefit from dexamethasone until that point.)

The recent study retractions in The Lancet and The New England Journal of Medicine have hurt public trust in medical research, especially in an environment where statements for or against a given drug often reflect political leanings. A cheap, effective, and uncontroversial drug that truly helps COVID-19 patients is the medical research world’s first step toward regaining its own health.

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Ben Daxon with team members from the COVID-19 Surge ICU (Handout)


A doctor goes to New York

One Minnesota doctor’s experience volunteering at the COVID-19 front lines for a week

On April 23, Ben Daxon, a critical care physician, donned scrubs and a scuba mask. Fitted with a 3D-printed adapter for a viral filter, the mask was “heavy, tight, suffocating,” he says. But it was necessary during Daxon’s shift working in one of six COVID-19 intensive care units at a Brooklyn, N.Y., hospital, where he volunteered for a week and where only curtains divided one critical patient from the next.

Daxon’s mask kept the coronavirus out. It also blocked his voice. By the end of his first shift, he had a sore throat from yelling through the mask. After that, he instead used an N95 mask, which rubbed his nose until it bled.

Ordinarily, Daxon, 36, works as an intensivist at Mayo Clinic in Rochester, Minn., and also logs in to satellite hospitals, communicating with patients remotely by video link. With the spread of COVID-19, especially in hot spots like New York City, Daxon wanted to do more than answer questions from his computer.

After halting elective surgeries and procedures, Daxon’s employer furloughed or cut the pay of 30,000 employees. Meanwhile, a friend who was volunteering in New York told him how bad the situation was there. Healthcare workers were making do with a lack of personal protective equipment. Some had contracted the virus themselves. Many were working overtime and outside their area of practice. “They needed help yesterday,” Daxon realized.

Of the 24 patients on his floor, almost all had multi-organ failure.

Ben and his wife, Amanda, decided Ben needed to go to the front lines. Amanda, a high-school literature teacher, would keep things running on the home front and stay with the Daxons’ three children, ages 6, 4, and 2. Before he left, Amanda asked her husband if his will was up to date. “We weren’t naïve to how serious this was,” she says.

At the Brooklyn hospital, the COVID-19 unit was “the sickest ICU I had ever seen,” Daxon says. Of the 24 patients on his floor, almost all had multi-organ failure and were “on the brink of death.” He realized many of his patients were going to die, but decided, “I was going to do everything I could to stop it.” 

During one shift, he noticed a patient’s ventilator was delivering very small breaths. An ultrasound showed that the man had a tear in his lung. His ventilator was still pumping, but the air was trapped. The air pressure could eventually crush the man’s healthy lung and heart. Daxon had to perform an emergency procedure: insert needles into the patient’s chest to let the trapped air escape. He did, and the patient improved shortly after. It was the first time Daxon had ever performed the procedure.

He had to make other difficult, urgent decisions. Two patients needed dialysis machines (some COVID-19 patients experience kidney failure), but the hospital didn’t have any to spare. Daxon decided one patient was doing well enough to take her machine and give it to the person who needed it more.

Another complication: The hospital’s ventilators were old, subpar models provided by FEMA. Though every patient at the hospital had a ventilator, the machines didn’t work well. “It’s like giving a surgeon a machete when they need a scalpel,” says Daxon.

Being able to talk medical jargon with Amanda, a former ICU nurse, helped Ben process his experiences in New York. When his night shift ended at 7 a.m. each day, he’d call his wife, walk back to his hotel, and write a journal entry.

Ordinarily Daxon doesn’t finish a week working in the ICU without questioning some of his decisions. Since returning from New York, new medical evidence (including studies suggesting ventilators might be overused on COVID-19 patients) makes him wish he had done some things differently. Would his patients have fared better with a different treatment approach? Doctors with more experience than him have wondered the same thing, he says.

Daxon recalls four or five patients died during his volunteer week, but after his return home, he heard good news about two others: Doctors extubated one and discharged the other. “It’s hard to describe to people outside of the ICU how rewarding that is,” says Daxon.

Even though he’s home now, he still thinks about the doctors and nurses on the front lines: “I’m in my kitchen. Those people are still there.”

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Troubling retractions

Peer review failures by top science journals may undermine trust in medical science

The Lancet and The New England Journal of Medicine—among the world’s most prestigious science journals—each retracted a headlining study about COVID-19 on Thursday. The implications extend beyond those journals, though, and threaten to erode public trust in medical research at a time when it is most needed.

The Lancet’s study, the better-known of the two, claimed to have analyzed over 96,000 COVID-19 patients from 671 different hospitals. On the strength of this seeming mountain of data, the authors stated that the drugs hydroxychloroquine and chloroquine did not help patients, and that in fact they often harmed patients. The study was published May 22, and its conclusions affected other studies: When researchers learn their projects would harm patients, they are ethically obligated to stop.

Thus, the World Health Organization’s “Solidarity” trial, proceeding in over 100 countries, paused its hydroxychloroquine arm. The ASCOT trial, seeking to recruit 2,500 patients in Australia and Asia, also paused.

But soon, an impromptu online peer-review effort sprang up around the Lancet study, identifying major red flags: For example, the study claimed the prevalence of smoking was almost uniform at about 10 percent worldwide. (World Health Organization data show wide differences, with 13.9 percent of Africans smoking tobacco, 28.7 percent of Europeans, and so forth.) The Lancet study also had only four authors, a number more often associated with small studies at a single institution than with massive studies analyzing tens of thousands of patients. 

Surgisphere Corp., a company founded by study co-author Sapan Desai, claimed to have the data, yet said it was prohibited by “data sharing agreements” from allowing anyone else to evaluate or verify the analysis—an extremely unusual way of handling data for groundbreaking research. Even more basic questions remained unanswered: For one, how could a tiny company persuade hundreds of hospitals on six continents to share patient data?

Hundreds of researchers signed an open letter, posted online May 28, that questioned the Lancet study. On Wednesday the research journal published an “expression of concern” alluding to “important scientific questions [that] have been raised.” Then, the next day, three of the four study co-authors asked the journal to retract the study.

How did it get published at all? Lancet editor Richard Horton has published editorials criticizing President Donald Trump, who has promoted the use of hydroxychloroquine against COVID-19. But even if political leanings influenced his decision to accept the Surgisphere study, politics can’t explain why The New England Journal of Medicine also accepted a recent Surgisphere study about less controversial medications. That study, published online May 1, analyzed whether two common classes of blood-pressure medication increased the health risk in patients with COVID-19 and concluded they do not. This week, as critics questioned Surgisphere’s reliability, the NEJM announced its own “expression of concern.” On Thursday it retracted the article.

Even that was not the end of Surgisphere’s impact: A third journal posted a preprint article online (since deleted, but archived here) relying on Surgisphere’s data and endorsing the use of ivermectin—a treatment for worms and other parasites—against the coronavirus.

All this matters, not simply because the public needs to be able to trust the research behind its medical care, but also because this bad research stopped better research from proceeding. The World Health Organization trial and the ASCOT trial have resumed, but will patients be willing to join? Or will they view the Surgisphere data as reason to stay away? What of the patients in South America now turning to ivermectin on the basis of a study since deleted?

Above all, how did a tiny startup’s hand-waving explanation fool the two most influential medical journals in the world—and a third journal for good measure—at the same time? Did Surgisphere’s talk of “machine learning” and “actionable data insights” dazzle the journal editors into ignoring the red flags? 

Questions outnumber answers right now. Those answers will be crucial to reestablishing public trust in medical research.

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