Mainstream Science, and Governments, Rejected Early Evidence of Symptomless Transmission

(p. 1) MUNICH — Dr. Camilla Rothe was about to leave for dinner when the government laboratory called with the surprising test result. Positive. It was Jan. 27 [2020]. She had just discovered Germany’s first case of the new coronavirus.

But the diagnosis made no sense. Her patient, a businessman from a nearby auto parts company, could have been infected by only one person: a colleague visiting from China. And that colleague should not have been contagious.

The visitor had seemed perfectly healthy during her stay in Germany. No coughing or sneezing, no signs of fatigue or fever during two days of long meetings. She told colleagues that she had started feeling ill after the flight back to China. Days later, she tested positive for the coronavirus.

. . .

Dr. Rothe and her colleagues were among the first to warn the world. But even as evidence accumulated from other scientists, leading health officials expressed unwavering confidence that symptomless spreading was not important.

In the days and weeks to come, politicians, public health officials and rival academics disparaged or ignored the Munich team. Some actively worked to undermine the warnings at a crucial moment, as the disease was spreading unnoticed in French churches, Italian soccer stadiums and Austrian ski bars. A cruise ship, the Diamond Princess, would become a deadly harbinger of symptomless spreading.

. . .

(p. 10) Though estimates vary, models using data from Hong Kong, Singapore and China suggest that 30 to 60 percent of spreading occurs when people have no symptoms.

. . .

After two lengthy phone calls with the woman, doctors at the Robert Koch Institute were convinced that she had simply failed to recognize her symptoms. They wrote to the editor of The New England Journal of Medicine, casting doubt on Dr. Rothe’s findings.

Editors there decided that the dispute amounted to hairsplitting. If it took a lengthy interview to identify symptoms, how could anyone be expected to do it in the real world?

“The question was whether she had something consistent with Covid-19 or that anyone would have recognized at the time was Covid-19,” said Dr. Eric Rubin, the journal’s editor.

“The answer seemed to be no.”

The journal did not publish the letter. But that would not be the end of it.

. . .

On Monday, Feb. 3, the journal Science published an article calling Dr. Rothe’s report “flawed.” Science reported that the Robert Koch Institute had written to the New England Journal to dispute her findings and correct an error.

. . .

Dr. Rothe’s report quickly became a symbol of rushed research. Scientists said she should have talked to the Chinese patient herself before publishing, and that the omission had undermined her team’s work. On Twitter, she and her colleagues were disparaged by scientists and armchair experts alike.

“It broke over us like a complete tsunami,” Dr. Hoelscher said.

. . .

If Dr. Rothe’s paper had implied that governments might need to do more against Covid-19, the pushback from the Robert Koch Institute was an implicit defense of the conventional thinking.

Sweden’s public health agency declared that Dr. Rothe’s report had contained major errors. The agency’s website said, unequivocally, that “there is no evidence that people are infectious during the incubation period” — an assertion that would remain online in some form for months.

French health officials, too, left no room for debate: “A person is contagious only when symptoms appear,” a government flyer read. “No symptoms = no risk of being contagious.”

. . .

(p. 11) Dr. Rothe, . . ., was shaken. She could not understand why much of the scientific establishment seemed eager to play down the risk.

“All you need is a pair of eyes,” she said. “You don’t need rocket-science virology.”

. . .

While public health officials hesitated, some doctors acted. At a conference in Seattle in mid-February, Jeffrey Shaman, a Columbia University professor, said his research suggested that Covid-19’s rapid spread could only be explained if there were infectious patients with unremarkable symptoms or no symptoms at all.

In the audience that day was Steven Chu, the Nobel-winning physicist and former U.S. energy secretary. “If left to its own devices, this disease will spread through the whole population,” he remembers Professor Shaman warning.

Afterward, Dr. Chu began insisting that healthy colleagues at his Stanford University laboratory wear masks. Doctors in Cambridge, England, concluded that asymptomatic transmission was a big source of infection and advised local health workers and patients to wear masks, well before the British government acknowledged the risk of silent spreaders.

The American authorities, faced with a shortage, actively discouraged the public from buying masks. “Seriously people — STOP BUYING MASKS!” Surgeon General Jerome M. Adams tweeted on Feb. 29.

. . .

By the end of the month [March 2020], the U.S. Centers for Disease Control announced it was rethinking its policy on masks. It concluded that up to 25 percent of patients might have no symptoms.

Since then, the C.D.C., governments around the world and, finally, the World Health Organization have recommended that people wear masks in public.

Still, the W.H.O. is sending confusing signals. Earlier this month, Dr. Van Kerkhove, the technical lead, repeated that transmission from asymptomatic patients was “very rare.” After an outcry from doctors, the agency said there had been a misunderstanding.

“In all honesty, we don’t have a clear picture on this yet,” Dr. Van Kerkhove said. She said she had been referring to a few studies showing limited transmission from asymptomatic patients.

Recent internet ads confused the matter even more. A Google search in mid-June for studies on asymptomatic transmission returned a W.H.O. advertisement titled: “People With No Symptoms — Rarely Spread Coronavirus.”

For the full story, see:

Matt Apuzzo, Selam Gebrekidan and David D. Kirkpatrick. “How the World Missed Covid’s Symptom-Free Carriers.” The New York Times, First Section (Sunday, June 28, 2020): 1 & 10-11.

(Note: ellipses, and bracketed dates, added.)

(Note: the online version of the story was updated June 27, 2020 and has the title “How the World Missed Covid-19’s Silent Spread.”)

Modern Physics Puts Elegance and Beauty Over Practical Value

(p. C9) Fundamental physics, says David Lindley, has lost its way. “I am ready to declare that research in this area, no matter its intellectual pedigree and exacting demands, is better thought of not as science but as philosophy.” His book aims to show how physics emerged out of airy speculation in the 17th century and, in recent years, has sunk back into it. “The Dream Universe” is not a book that will please philosophers, nor indeed historians, though physicists will find the argument a familiar one.

The problem, says its author, has been an excessive reliance on “mathematical elegance and beauty and whatnot” in fields such as “particle physics, the unification of gravity with quantum mechanics, and cosmology.” . . .

“The Higgs mechanism is no one’s idea of beautiful mathematics,” Mr. Lindley writes. “There’s nothing natural or inevitable about it, certainly nothing elegant. But it does its job.” The same applies, it appears, to one of the biggest breakthroughs in astronomy of recent decades, the confirmed reality of a previously theorized quantity driving universal expansion at an accelerating rate. “The beauty or otherwise of the cosmological constant is a non-issue,” the author writes. “It has practical value, and that’s what matters.”

. . .

The modern rot set in, he maintains, with theoreticians such as Hermann Weyl and Paul Dirac, who spoke of beauty as well as truth in physics. “Galileo would have been aghast,” Mr. Lindley writes. “He had no patience with mystical blather.”

. . .

Mr. Lindley complains that “the more physics pushes into the subatomic world, the more arcane the mathematical tools it draws upon.”

For the full review, see:

Andrew Crumey. “Pulling on a String.” The Wall Street Journal (Saturday, June 13, 2020): C9.

(Note: ellipses added.)

(Note: the online version of the review has the date June 12, 2020, and has the title “‘The Dream Universe’ Review: Pulling on a String.”)

The book under review, is:

Lindley, David. The Dream Universe: How Fundamental Physics Lost Its Way. New York: Doubleday, 2020.

Oliver Williamson’s Subtle Attempt to Get Pablo Spiller to Turn Down the Music

Several years ago, I presented a paper in an economic methodology session at the AEA in which Williamson also presented a paper. He was a fellow pluralist in method. I think his work deserves more attention than I have given it. The profession will be worse for his absence.

(p. A9) Building on the work of Ronald Coase, Dr. Williamson developed transaction-cost economics, examining costs that go beyond the price of a good or service.

. . .

Some of Dr. Williamson’s thinking took shape when he worked for the Justice Department’s antitrust division in 1966 and 1967.

The department had accused Schwinn & Co. of restraining trade by limiting the retailing of its bicycles to authorized merchants. The conventional wisdom among antitrust enforcers was that such arrangements could be explained only as an effort to reduce competition.

Dr. Williamson found the question more complicated and argued that Schwinn’s motive might be to reduce costs. For instance, a restricted number of retailers would make it less costly to control quality and agree on how to share advertising expenses. The resulting increase in efficiency could benefit consumers.

. . .

Pablo Spiller, a friend and Berkeley colleague who lived across the street from Dr. Williamson, recalled that he spoke precisely but not always directly. One night Dr. Spiller was playing music a bit too loudly. Dr. Williamson called. Rather than mentioning the volume, he said: “You know, I actually like the current song more than all the previous ones.”

For the full obituary, see:

James R. Hagerty. “Economist Explored Inner Life of Firms.” The Wall Street Journal (Tuesday, June 6, 2020): A9.

(Note: ellipses added.)

(Note: the online version of the obituary has the date June 4, 2020, and the title “Oliver Williamson, Nobel Economics Winner, Studied Inner Life of Firms.”)

Hydroxychloroquine Clinical Trials Suspended on Basis of Lancet Article Containing “Major Inconsistencies”

(p. A11) A group of scientists who raised questions last week about a study in The Lancet about the use of antimalarial drugs in coronavirus patients have now objected to another paper about blood pressure medicines in the New England Journal of Medicine, which was published by some of the same authors and relied on the same data registry.

Moments after their open letter was posted online Tuesday morning [June 2, 2020], the editors of the N.E.J.M. posted an “expression of concern” about the paper, and said they had asked the paper’s authors to provide evidence that the data are reliable.

The Lancet followed later in the day with a statement about its own concerns regarding the malarial drugs paper, saying that the editors have commissioned an independent audit of the data.

. . .

In their letter to the N.E.J.M., critics of the work wrote: “Serious, and as yet unanswered, concerns have been raised about the integrity and provenance of these data.”

The letter points out “major inconsistencies” between the number of coronavirus cases recorded in some countries during the study period and the number of patient outcomes reported by the researchers over the same period.

. . .

Many of the scientists who first raised concerns about the database are involved in clinical trials of chloroquine and hydroxychloroquine, and they were forced to pause the studies for safety reviews after The Lancet study was published.

James Watson, a senior scientist with MORU Tropical Health Network, said his unit had to immediately suspend work on a large randomized clinical trial to see if chloroquine or hydroxychloroquine can protect health care workers exposed on the job to the coronavirus from infection.

“I saw very quickly this paper didn’t hold up to much scrutiny at all,” he said. “We started wondering, ‘Who’s been collecting this data, and where did it come from?’ We were quite surprised to see a global study with only four authors listed and no acknowledgment of anyone else.”

. . .

David Glidden, a professor of biostatistics at University of California, San Francisco, who reads all new publications about Covid-19 antiviral therapies as a member of a National Institutes of Health clinical guidelines panel, said he was immediately struck by the vagueness of the descriptions in both papers.

For the full story, see:

Roni Caryn Rabin. “Scientists Question Medical Data From Single Company Used in Two Studies.” The New York Times (Wednesday, June 3, 2020): A11.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the article was updated June 2, 2020, and had the title “Scientists Question Medical Data Used in Second Coronavirus Study.”)

Trump Walks the Walk on Hydroxychloroquine

(p. A6) WASHINGTON—President Trump said he is taking hydroxychloroquine, an antimalarial drug that he has cited as a possible defense against the novel coronavirus but that some scientists have cautioned needs further study and could be dangerous.

“I happen to be taking it, hydroxychloroquine,” he told reporters at the White House on Monday. He said he had consulted with the White House doctor and suggested he is taking the drug as a preventive measure. Mr. Trump said he has been checked regularly for Covid-19, has tested negative and has no symptoms. He said he has been taking hydroxychloroquine for about a week and a half.

. . .

On Monday [May 18, 2020], Mr. Trump continued to stress anecdotal evidence in favor of the drug and told reporters, “I was just waiting to see your eyes light up when I said this.” He also expressed confidence in the drug’s safety. “I’m not going to get hurt by it. It’s been around for 40 years for malaria, for lupus, for other things.”

For the full story, see:

Catherine Lucey, Jared S. Hopkins. “President Trump Says He Is Taking Hydroxychloroquine as Preventive.” The Wall Street Journal (Tuesday, May 19, 2020): A6.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story has the date May 18, 2020, and has the title “Trump Says He Takes Contested Drug for Prevention.”)

The key reference on advocates of a drug who take it first themselves, without confirmation from randomized double-blind clinical trials, is:

Altman, Lawrence K. Who Goes First?: The Story of Self-Experimentation in Medicine. Berkeley, CA: University of California Press, 1998.

Physicians Fighting Covid-19 Use Social Media “to Share Improvised Solutions”

(p. A9) In mid-March [2020], as U.S. hospitals scrambled for ventilators to treat a surge of coronavirus cases, a Vermont pulmonologist proposed a different treatment on a blog popular with emergency-medicine doctors.

Joshua Farkas observed in the post on the EMCrit blog that many Covid-19 patients seemed to benefit from less-invasive alternatives to help their breathing, including pressure therapy used to treat sleep apnea—sometimes referred to as CPAP, for continuous positive airway pressure.

. . .

The post helped galvanize an emerging theory about the treatment of Covid-19 patients, which in recent weeks has taken hold in U.S. hospitals. In New York City, where ventilators are in perilously short supply, doctors say they have since embraced CPAP and other treatments to improve breathing in Covid-19 patients.

The shift is one example of how health-care workers are writing the playbook for treating coronavirus patients on the fly, knowing they can’t wait for peer-reviewed articles or studies in established medical journals. Instead they are tapping into social media, podcasts, inside-baseball medical blogs and text-message groups to share improvised solutions to supply shortages and patient care, forcing hospitals to quickly re-evaluate their practices.

“This has been a rapidly evolving process,” said Dr. Farkas, who has treated Covid-19 patients in the intensive-care unit at the University of Vermont in Burlington. “As we struggle with how to treat a disease that so recently was totally unknown, this rapid exchange and updating of information is crucial.”

. . .

Last week, Michelle Romeo, a chief emergency-medicine resident at NYU Langone and Bellevue hospital in Manhattan, tweeted photos of a jury-rigged breathing device involving a mask used for BiPAP—an airway pressure therapy similar to CPAP.

At Mount Sinai Hospital in Manhattan, pulmonologists worked with the hospital’s sleep lab to figure out a way to use BiPAP machines like a ventilator. The result was posted on Reddit, and got “all kinds of different responses,” said Valerie Burgos-Kneeland, a registered nurse in the hospital’s Medical Intensive Care Unit. “It’s kind of been an opportunity for people to get creative.”

For the full story, see:

Rebecca Davis O’Brien. “Doctors Improvise, Share Treatments.” The Wall Street Journal (Friday, April 10, 2020): A9.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story has the date April 9, 2020, and has the title “Doctors Are Improvising Coronavirus Treatments, Then Quickly Sharing Them.”)

“Real World Evidence” on Effectiveness of Experimental Drugs Can Be Extracted From Electronic Health Records

(p. A7) . . . analysis of compassionate-use data, about the experimental drug remdesivir from Gilead Sciences Inc. published in the New England Journal of Medicine, came under criticism. Scientists pointed out that the Covid-19 patients received the drug in centers around the world where care may have differed, data on some patients was incomplete and there was no comparison group.

That study’s first author, Jonathan Grein, of Cedars-Sinai Medical Center in Los Angeles, said given how little is known about the coronavirus and how to treat it, “I think at this point any information is potentially helpful.” He said the study, funded by Gilead Sciences, noted the findings were limited and preliminary. “It is a starting point, an opportunity to aggregate our initial experiences,” he said.

. . .

The FDA . . . has worked closely with companies trying to extract “real world evidence” about patients’ experiences with new or experimental drugs from sources such as electronic health records.

For the full story, see:

Amy Dockser Marcus. “Hundreds Get Plasma in National Study.” The Wall Street Journal (Wednesday, April 22, 2020): A7.

(Note: ellipses added.)

(Note: the online version of the story has the date April 21, 2020, and has the title “Hundreds Receive Plasma From Recovered Coronavirus Patients in National Study.”)

Early Promising Results from Gilead-Sponsored Study on Remdesivir

(p. B3) A doctor in Chicago told colleagues that Gilead’s drug remdesivir appeared to help many patients enrolled in a clinical trial site at the University of Chicago Medicine hospital, according to a news report in online health publication STAT, which cited a video of the remarks. The doctor said that the hospital had enrolled 125 patients in two remdesivir studies sponsored by Gilead, and that most had been discharged from the hospital, and two had died.

. . .

“Partial data from an ongoing clinical trial is by definition incomplete and should never be used to draw conclusions about the safety or efficacy of a potential treatment that is under investigation,” a University of Chicago spokeswoman said in an email. “Drawing any conclusions at this point is premature and scientifically unsound.”

. . .

Last week, Gilead reported in the New England Journal of Medicine that remdesivir showed encouraging results in treating 53 patients with severe Covid-19 symptoms. The patients were given the drug under so-called compassionate use, which allows for doctors to request unapproved drugs for patients in emergency situations.

Of the 53 compassionate use patients who received remdesivir, nearly half were discharged from the hospital and seven patients died, or 13% of the total, according to the New England Journal paper. Of 30 patients using breathing tubes connected to ventilators, 17 had their tubes disconnected after remdesivir treatment.

For the full story, see:

Joseph Walker. “Gilead Shares Up 9.7% On Encouraging Signs In Covid-19 Drug Trial.” The Wall Street Journal (Saturday, April 18, 2020): B3.

(Note: ellipses added.)

(Note: the online version of the story has the date April 17, 2020, and has the title “Coronavirus Drug Report, Though Inconclusive, Sends Gilead Higher.” Where the versions differ, the passages quoted above follow the somewhat longer online version.)

A Map as Large as the Territory It Represents

(p. A4) As more reliable data comes in, said Dr. Spiegelhalter, “the Covid-19 pandemic is rapidly becoming a constrained problem.”

. . .

Statistical science, he said, “is a machine, in a sense, to turn the variability that we see in the world — the unpredictability, the enormous amount of scatter and randomness that we see around us — into a tool that can quantify our uncertainty about facts and numbers and science.”

But as he acknowledged in his book, “The Art of Statistics,” models “are simplifications of the real world — they are the maps not the territory.” (This is reminiscent of Jorge Luis Borges’s story, “On Exactitude in Science,” about a map growing as large as the territory it was meant to represent.)

For the full review, see:

Siobhan Roberts. “Embracing the Uncertainties of the Pandemic.” The New York Times (Wednesday, April 8, 2020): A4.

(Note: ellipsis added.)

(Note: the online version of the review has the date April 7, and has the title “Embracing the Uncertainties.”)

The Spiegelhalter book mentioned above, is:

Spiegelhalter, David. The Art of Statistics: How to Learn from Data. New York: Basic Books, 2019.

“A Clinical Hunch by a Lot of Really Smart People”

(p. A1) Thomas Oxley wasn’t even on call the day he received the page to come to Mount Sinai Beth Israel Hospital in Manhattan. There weren’t enough doctors to treat all the emergency stroke patients, and he was needed in the operating room.

The patient’s chart appeared unremarkable at first glance. He took no medications and had no history of chronic conditions. He had been feeling fine, hanging out at home during the lockdown like the rest of the country, when suddenly, he had trouble talking and moving the right side of his body. Imaging showed a large blockage on the left side of his head.

Oxley gasped when he got to the patient’s age and covid-19 status: 44, positive.

The man was among several recent stroke patients in their 30s to 40s who were all infected with the novel coronavirus. The median age for that type of severe stroke is 74.

As Oxley, an interventional neurologist, began the procedure to remove the clot, he observed something he had never seen before. On the monitors, the brain typically shows up as a tangle of black squiggles – “like a can of spaghetti,” he said – that provide a map of blood vessels. A clot shows up as a blank spot. As he used a needlelike device to pull out the clot, he saw new clots forming in real-time around it.

“This is crazy,” he remembers telling his boss.

A SURGE

Reports of strokes in the young and middle-aged – not just at Mount Sinai but in many other hospitals in communities hit hard by the coronavirus – are the latest twist in our evolving understanding of its connected disease, covid-19. Even as the virus has infected nearly 2.8 million people worldwide and killed 195,000 as of Friday, its biological mechanisms continue to elude top scientific minds. Once thought to be a pathogen that primarily attacks the lungs, it has turned out to be a much more formidable foe – impacting nearly every major organ system in the body.

Until recently, there was little hard data on strokes and covid-19.

There was one report out of Wuhan, China, that showed that some hospitalized patients had experienced strokes but many of those were seriously ill and elderly. But the linkage was considered more of “a clinical hunch by a lot of really smart people,” said Sherry H-Y Chou, a University of Pittsburgh Medical Center neurologist and critical care doctor.

Now for the first time, three large U.S. medical centers are preparing to publish data on the stroke phenomenon. The numbers are small, only a few dozen per location, but they provide new insights into what the virus does to our bodies.

For the full story, see:

Ariana Eunjung Cha. “Strokes Are Striking Younger, Symptomless COVID-19 Victims.” The Washington Post (Saturday, April 25, 2020): A1.

(Note: bold in original.)

(Note: some of the above quote may have been continued onto a later page than A1.)

Seeing Patterns Is Important Knowledge

Collecting, categorizing, and taxonomizing, are early steps toward scientific knowledge, as the example below illustrates. But these activities are often dismissed or ridiculed by members of the scientific establishment.

(p. A23) In the 1970s, Dr. Melzack turned to another problem he had been thinking about for years: pain measurement. At the time, doctors had only very crude instruments, like simply asking people to rate their pain level on a scale from 1 to 10 (a method that is still in use). As a young researcher, Dr. Melzack had worked in a chronic pain clinic and befriended a 70-year-old woman with diabetes.

“She was a highly intelligent person with a good vocabulary, and I began to collect her descriptive words about pain, like ‘burning,’ ‘shooting,’ ‘horrible’ and ‘excruciating,’” he told McGill Reporter in a 2008 interview.

He continued to build his adjective collection by listening to many patients’ descriptions and, working with a statistician, divided them into 20 categories, each describing a particular kind of pain: “tugging,” “pulling” and “wrenching” in one category, for instance, and “pinching,” “pressing” and “gnawing” in another.

This descriptive catalog, published in the journal Pain in 1975, became the McGill Pain Questionnaire. It soon became a standard measure worldwide, deeply enriching the conversations doctors have with their patients, and in many cases helping with diagnosis.

For the full obituary, see:

Benedict Carey. “Ronald Melzack, Cartographer of Pain, Is Dead at 90.” The New York Times (Monday, January 13, 2020): A23.

(Note: the online version of the obituary has the date Jan. 12, 2020, and has the same title as the print version.)