Isegoria

Testing residents of San Francisco’s Mission District for Covid-19 revealed that the data you get when you go out and test people without symptoms is different from the data you get when you only test those who show up in a hospital:

Slightly more than 2% of the people tested in the four square blocks currently have the coronavirus, for instance. Only 1 in 10 of them has a fever and most have no symptoms at all — which is to say that, absent the testing, they’d probably still be walking around and infecting people without knowing it.

There was more. Of the 981 white people tested, zero have the virus. Latinos are only 44% of the study but 95% of the positives. Men are a bit more than half of the sample but 75% of the positives. Just over half of the people tested say they’re unable to work from home — but that group registers 90% positive. Being in a crowded house appears to be a problem: nearly 30% of the positives come from households of more than five people, though those households make up only 15% of the population. Being poor is a bigger problem: people earning less than $50,000 a year are 89% of the positives, though only 39% of the group studied. Only a quarter of the people with the virus have a primary care doctor. Six of the people with the virus still haven’t been located by the researchers, and informed that they’re ill.

Do you understand what a “95% confidence interval” means?, Peter Attia asks:

1. Distance from earth to nearest star (excluding sun), in light-years
   95% confidence interval: [ _________ , _________ ]
2. GDP of Mongolia, in USD
   95% confidence interval: [ _________ , _________ ]
3. Height of tallest man in recorded history, in inches
   95% confidence interval: [ _________ , _________ ]
4. Depth of deepest part of Pacific Ocean, in meters
   95% confidence interval: [ _________ , _________ ]
5. Average distance from earth to moon, in miles
   95% confidence interval: [ _________ , _________ ]
6. Population of Russia in 2019
   95% confidence interval: [ _________ , _________ ]
7. Maximum number of passengers carried on Emirates A380 aircraft (two-class layout)
   95% confidence interval: [ _________ , _________ ]
8. Number of passengers who died on the Titanic
   95% confidence interval: [ _________ , _________ ]
9. Market capitalization of Apple on the day Steve Jobs died, in USD
   95% confidence interval: [ _________ , _________ ]
10. Fastest lap time in an F1 car around the Monaco circuit, in min:sec
    95% confidence interval: [ _________ , _________ ]
11. Number of regular season goals scored by Wayne Gretzky in his NHL career
    95% confidence interval: [ _________ , _________ ]
12. NASAs budget for the year 2019, in USD
    95% confidence interval: [ _________ , _________ ]
13. Number of Big Macs sold globally in a year (on average) by McDonalds
    95% confidence interval: [ _________ , _________ ]
14. Number of students from China attending U.S. colleges in the 2018-2019 academic year
    95% confidence interval: [ _________ , _________ ]
15. Total number of passengers flying domestically on U.S. airlines in 2019
    95% confidence interval: [ _________ , _________ ]
16. Amount of coal produced by U.S. mines in 2019, in pounds
    95% confidence interval: [ _________ , _________ ]
17. Breeds eligible to compete at the 144th Westminster Kennel Dog Show
    95% confidence interval: [ _________ , _________ ]
18. Number of total worldwide searches processed by Google each day
    95% confidence interval: [ _________ , _________ ]
19. Full weight (including planes, ammunition, people) of a Nimitz-class aircraft carrier, in pounds
    95% confidence interval: [ _________ , _________ ]
20. Number of times that the name “Jesus” appears in the King James bible
    95% confidence interval: [ _________ , _________ ]

(Answers.)

This is one of the key concepts in How to Measure Anything: Finding the Value of Intangibles in Business, by Douglas W. Hubbard.

Matt Ridley is rationally optimistic that within a month or two, one of the 30 or more therapies for COVID-19 currently being tested is likely to prove effective and safe:

The biological problem, as Amesh Adalja of Johns Hopkins University argued in a prescient call to arms just before the pandemic struck, is that viruses do not have their own biochemistry, because they borrow ours.

So unlike, say, tuberculosis, there is not much to attack.

[...]

The problem is that viruses differ from each other, so treatments that work for one seldom work for another. The drugs that work against HIV-1, the main cause of Aids, sometimes do not even work against HIV-2,a milder version of the virus. Those that work against herpes don’t kill the very similar cytomegalovirus. One influenza drug works only against influenza A and not B. One antiviral kills just one genotype of hepatitis C. It is no coincidence that the antiviral treatments capable of attacking more kinds of virus, such as ribavirin, are also the most toxic to the patient, because they tend to attack the machinery of the host as well.

[...]

Protease inhibitors tend to be highly specific, so the HIV ones are not necessarily useful against Sars-CoV-2. A different protease inhibitor, however, called camostat mesylate, already approved for use in Japan as a treatment for pancreatitis, is showing promise. It was found in 2012 to work against Sars in the laboratory.

[...]

In 2015 remdesivir worked against ebola in monkeys, but in the 2018 epidemic in Congo it failed to make sufficient difference to ebola patients compared with other treatments. [...] However, remdesivir is unlikely to be the silver bullet because it is probably best if taken early in the infection, but you would not want to take it if you had a mild bout. It’s administered intravenously and has some nasty side effects.

[...]

There is more hope for favipiravir, sold as Avigan, one of the few antiviral treatments showing promise against more than one kind of virus. Bizarrely, it’s made by a subsidiary of Fujifilm, which diversified into chemicals and pharmaceuticals to avoid the fate of Kodak. Invented during the search for a herpes cure, it has since shown promise against influenza. Though good in the laboratory, it was only partially effective against ebola in Guinea in 2014, but initial trials on 80 coronavirus patients in China this year have suggested that it can speed up the recovery time for Covid patients, perhaps cutting it in half. So Fujifilm is now rushing to increase production and the drug has been cleared for use against coronavirus in Japan. The good news is it’s a pill, not an injection, and has few side effects except in pregnant women, where it is not safe.

[...]

If chemical treatments do not work, so-called monoclonal antibodies might. If someone recovers, their own body produces antibodies that smother the virus. These days it’s possible to mass-produce exact copies of the antibodies that work, using genetic engineering. Known as monoclonal antibodies, they proved to be the best way to treat ebola patients in Congo in 2018, when the US biotech firm Regeneron came up with a cocktail of human antibodies using genetically engineered mice. Regeneron has rushed a new cocktail of Covid-19 antibodies through the same procedure and hopes to have it ready to test in early summer. Scaling it up for mass production will not, however, be as easy as it would for a chemical pill.

[...]

It is not yet clear how [hydroxychloroquine] works: after all, malaria is neither a virus nor a bacterium, but a parasite. But hydroxychloroquine is used against rheumatoid arthritis and the autoimmune disease lupus. In the laboratory, it does seem to slow and inhibit the infection of cells by this coronavirus.

Hydroxychloroquine also tends to team up with the metal zinc and there are persistent and reliable reports that zinc either stops viruses replicating or helps the immune response to them. A gold-standard review of clinical trials found that zinc lozenges do shorten the duration of a cold by somehow interfering with virus replication. This does not just seem to be a diminishing-returns effect whereby having too little zinc, like having too little vitamin D, is bad, but once you have enough, having even more is no better. But if it is, up to a quarter of people in developing countries are deficient in zinc, and zinc deficiency is not uncommon among the elderly in western countries, so this may be part of the explanation why some elderly people are more seriously affected. In short, zinc supplements as a cheap medication, unrewarding to big pharma and therefore neglected, cannot be ruled out as a useful thing to try. Intriguingly, too much zinc kills your sense of taste, as does Covid-19 in many cases.

He has a new book out, by the way — How Innovation Works: And Why It Flourishes in Freedom.

In 1899, a German bacteriologist named Carl Flügge proved that microbes can be transmitted ballistically through large droplets emitted at high velocity from the mouth and nose:

His method for proving the existence of these “Flügge droplets” (as they came to be known) was to painstakingly count the microbe colonies growing on culture plates hit with the expelled secretions of infected lab subjects. It couldn’t have been pleasant work. But his discoveries saved countless lives. And more than 12 decades later, these large respiratory droplets have been identified as a transmission mode for COVID-19.

Flügge’s graduate students continued his work into the 20^th century, experimenting with different subjects expelling mucosalivary droplets in different ways. Eventually they determined, as a 1964 report in the Proceedings of the Royal Society of Medicine put it, that the quantity of expelled Flügge droplets varies markedly based on the manner of respiration: “Very few, if any… droplets are produced during quiet breathing, but [instead, they] are expelled during activities such as talking, coughing, blowing and sneezing.” A single heavy cough, it is now known, can expel as much as a quarter teaspoon of fluid in the form of Flügge droplets. And the higher the exit velocity of the cough, the larger the globules that can be expelled.

Yet if Flügge were with us today, he might be surprised by how little his science has been usefully advanced over the last few generations. As Lydia Bourouiba of the MIT Fluid Dynamics of Disease Transmission Laboratory recently noted in JAMA Insights, the basic framework used to represent human-to-human transmission of respiratory diseases such as COVID-19 remain rooted in the tuberculosis era. According to the binary model established in the 1930s, droplets typically are classified as either (1) large globules of the Flüggian variety—arcing through the air like a tennis ball until gravity brings them down to Earth; or (2) smaller particles, less than five to 10 micrometers in diameter (roughly a 10th the width of a human hair), which drift lazily through the air as fine aerosols.

In a fascinating paper published on March 26th, Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19, Bourouiba shows that analyzing a human sneeze is unusually difficult, even by the standards of fluid dynamics (whose mathematics I once modeled in my former capacity as an engineer and computer programmer). That’s because those mucosalivary droplets we emit are cocooned within a warm, moist enveloping gas cloud—Bourouiba calls it a “puff”—that protects the droplets from evaporation and allows even small globules to travel much farther than one might otherwise predict. The binary distinction between large and small droplets remains fundamental: Eventually, the big particles fall while the smaller ones don’t. But during those first fractions of a second when a sneeze (or cough, or shout) is expelled, Bourouiba shows, the enveloping gas sheath allows smaller particles to act, ballistically speaking, as if they were larger.

The science here is mind-bogglingly complex, because modeling the puff’s behaviour requires that Bourouiba and her team model not only the dynamics of the puff as it travels and dissipates, but also the biophysical and thermodynamic processes unfolding within the gas cloud. But the overall upshot is that such a puff “and its payload of pathogen-bearing droplets of all sizes” can travel seven to eight meters—about four times the length of the six-foot social-distancing buffer zone we’ve all been taught to enforce since mid-March.

Bourouiba’s research hits squarely on a blind spot in our knowledge of COVID-19. On one hand, scientists have an intimate molecule-by-molecule knowledge of the virus’s structure, its full genome having been sequenced months ago. On the other hand, the scientific and lay literature is bursting with epidemiological reports from just about every corner of the planet. But the nitty-gritty mechanics of actual disease transmission doesn’t take place on the microscopic scale of nucleic acids or on the gargantuan scale of whole nations. It takes place on the everyday face-to-face scale of inches and feet, as Flügge showed 121 years ago.

And it is on this crucial scale that our knowledge is thinnest. Despite the passage of four months since the first known human cases of COVID-19, our public-health officials remain committed to policies that reflect no clear understanding as to whether it is one-off ballistic droplet payloads or clouds of fine aerosols that pose the greatest risk—or even how these two modes compare to the possibility of indirect infection through contaminated surfaces (known as “fomites”).

Super-spreader events fit a pattern:

These parties, funerals, religious meet-ups and business networking sessions all seem to have involved the same type of behaviour: extended, close-range, face-to-face conversation—typically in crowded, socially animated spaces. This includes the many people infected by a bartender while being served at a raucous après ski venue in Austria, and party guests in Brazil greeting “each other with two kisses on the cheek [a local custom], hugs and handshakes.” The funerals in question are generally described as highly intimate and congested scenes of grieving among close friends and relatives. In the case of the SSE funeral in Albany, Georgia that devastated the local population, “people wiped tears away, and embraced, and blew their noses, and belted out hymns. They laughed, remembering. It was a big gathering, with upward of 200 mourners overflowing the memorial chapel, so people had to stand outside.”

With few exceptions, almost all of the SSEs took place indoors, where people tend to pack closer together in social situations, and where ventilation is poorer. (It is notable, for instance, that the notorious outbreak at an Austrian ski resort is connected to a bartender and not, say, a lift operator.) But generalizations in this area are complicated by the fact that some of the religious festivals described herein were mixed indoor/outdoor affairs. (Moreover, the February 19 SSE at San Siro stadium in Milan is also ambiguous, since that stadium has a roof over the seating area, but not over the field—and thousands of the fans spent hours bouncing around bars in and around Milan.)

The media accounts of these SSEs are full of descriptions in this vein. At a February 15 festival in Gangelt, a town in Germany’s tiny Heinsberg district, “beer and wine flowed aplenty as approximately 350 adults in fancy dress locked arms on long wooden benches and swayed to the rhythm of music provided by a live band. During an interval in the programme, guests got up to mingle with friends and relatives at other tables, greeting each other as Rhineland tradition commands, with a bützchen, or peck on the cheek.” Since that time, more than 40 Germans from the Heinsberg district have died. It’s been called “Germany’s Wuhan.”

[...]

When do COVID-19 SSEs happen? Based on the list I’ve assembled, the short answer is: Wherever and whenever people are up in each other’s faces, laughing, shouting, cheering, sobbing, singing, greeting, and praying. You don’t have to be a 19th-century German bacteriologist or MIT expert in mucosalivary ballistics to understand what this tells us about the most likely mode of transmission.

It’s worth scanning all the myriad forms of common human activity that aren’t represented among these listed SSEs: watching movies in a theater, being on a train or bus, attending theater, opera, or symphony (these latter activities may seem like rarified examples, but they are important once you take stock of all those wealthy infectees who got sick in March, and consider that New York City is a major COVID-19 hot spot). These are activities where people often find themselves surrounded by strangers in densely packed rooms—as with all those above-described SSEs—but, crucially, where attendees also are expected to sit still and talk in hushed tones.

The first recorded epidemics in New England killed many Indians more than a century before the Pilgrims set foot on Plymouth Rock:

In what is now Canada and Maine, contact with Europeans began at least in 1504 with the first documented French vessel on the Grand Banks. By 1519, more than 300 European ships made round trips to Newfoundland in the summer. All came to fish.

The European visitors brought with them diseases to which the Indians had no immunity, including smallpox, measles, tuberculosis, cholera and bubonic plague.

In 1586, a typhus epidemic devastated Maine’s Passamaquoddy Indians, among the first to make contact with Europeans.

In 1616, a terrible plaque swept the Massachusetts coast – perhaps smallpox, perhaps yellow fever, perhaps bubonic plague. It killed as many as 90 percent of the Massachusetts people and devastated the Pennacooks in New Hampshire and Massachusetts. It also felled the Agawam in Ipswich and the Naumkeag in Salem. And it cleared nearly all the Wampanoag along the coast from Plymouth to Boston.

Then a smallpox epidemic in 1633 killed many more Massachusetts and Narragansetts in Rhode Island.

And after the Pequot War, smallpox, diphtheria, flu and measles killed two-thirds of the Pequot-Mohegans in Connecticut.

Virginia Postrel walks through the history of medical face masks:

19th century

Fashionable women wear lacy veils to protect against dust, particularly from the disruptions of Georges-Eugene Haussmann’s remaking of Paris. As germ theory spreads, the fashion takes on a medical aura when researchers using microscopes find bacteria on dust particles.

In an 1878 article printed in the Hospital Gazette and in Scientific American, A.J. Jessup, a Westtown, New York, physician, recommends cotton masks to limit contagion during epidemics:

Thus we see that as quarantine and disinfection will certainly spread of contagion from patient to patient, may we not confidently hope, by preventing the entrance of germs into the lungs and blood, by a properly constructed filtering mask to yet witness the spectacle of a population walking about the streets of a cholera infested city, without fear of its infection however deadly. As a properly made cotton filter worn over the mouth and nose must shut out all atmospheric gems of the ordinary putrefactive kind. We may confidently assured that those of disease will be equally excluded.

He cites his experiments with test tubes with and without cotton stoppers. His idea does not catch on.

Early 20th century

Although the first study advocating the use of masks during surgery is published in 1897, they are rare at the turn of the century.

In 1905, Chicago physician Alice Hamilton publishes an article in the Journal of the American Medical Association, reporting on experiments measuring the amount of streptococci bacteria expelled when scarlet fever patients cough or cry. She also measures the strep bacteria from healthy doctors and nurses when they talk or cough, leading her to recommend masks during surgery.

“I was told by a student in a large medical college in Chicago,” she writes, “that he had often noticed at the clinics of a certain surgeon that, when the light was from a certain direction, he could see, from his seat in the amphitheater, a continuous spray of saliva coming from the mouth of the surgeon while he discoursed to the class and conducted his operation. Obviously, protection of the mouth, of some sort as to catch and impression the droplets of sputum, should be a routine precaution for surgeons and for surgical nurses during operations.”

In 1910, an epidemic of pneumonic plague strikes Manchuria. Appointed by the Chinese court to head anti-plague efforts, the Penang-born, Cambridge-educated physician Wu Lien-Teh (Wu Liande) argues that the disease is transmitted through airborne contact. To prevent its spread, he develops masks to be worn by medical personnel and the general public.

During the 1918 global flu epidemic, medical personnel routinely adopt masks to protect themselves, and many cities require them in public. In Seattle, where streetcars require all riders to have masks, the local Red Cross enlists 120 workers to turn out 260,000 masks in three days.

In the 1920s, masks are standard in operating rooms.

Hyperbaric Oxygen Therapy appears to be treating the hypoxemia and underlying pathology (lung inflammation) in COVID-19:

Recently, two articles published in China featured the application of hyperbaric oxygen therapy in patients with novel coronavirus 19 (COVID-19) pneumonia.

The first was a case report of a severely ill patient who was failing standard respiratory support (not intubated) and whose disease course was reversed with eight hyperbaric oxygen treatments (HBOTs) at 200 kPa/95 minutes total treatment time.

The second was a more severely afflicted patient on a ventilator with acute respiratory distress syndrom (ADRS) whose life was saved by the application of five HBOTs.

By direct voice and electronic communication with the authors/treating physicians this author has reviewed the data and treatment of four additional severely ill COVID-19 patients with bilateral ground glass opacities who were failing standard mask oxygen therapy, were treated with 3-5 HBOTs and discharged from the hospital to home.

The authors reported that they have safely treated an additional 29 less severe patients with the same outcome.

The five non-intubated patients had been on oxygen support for days to weeks with immediate pre-HBOT oxygen saturation levels as low as 70% on mask oxygen. With each once daily administration of HBOT the patients experienced sustained elevation of oxygen saturation and improvement in symptom that persisted to the following morning.

With just 3–8 HBOTs the patients were bridged through the hypoxemic crisis phase of the infection and successfully discharged from the hospital. The authors suggested that HBOT applied earlier in the disease process would prevent the deterioration that leads to the significant morbidity and mortality of COVID-19 infection.