COVID19 update, April 30, 2020: Remdesivir clinical trial; South Korea stats redux; miscellaneous updates

(1) Yesterday, the NIAID announced the results of the first large-scale Remdesivir clinical trial. It is not a “magic bullet”, but this is a milestone in that for the first time, any drug has been shown to have an unambiguous therapeutic advantage: it significantly accelerates recovery in severe COVID19 cases. (I would be very interested to know if administering it before the patient’s symptoms escalate would forestall the latter. That would be an even bigger game-changer.[*]) Gilead Scientific’s CEO was restrained but upbeat in an open letter.— clearly they are looking at licensing the drug for manufacturing by third parties, as they clearly do not have the in-house manufacturing base for the massive amounts that would have to be synthesized.

Recapping how remdesivir works: it effectively impersonates a letter of the genetic code, except without an attachment point for the next letter. So when RdRp (RNA-dependent RNA polymerase) starts copying the genome, copying breaks off if the “imposter” letter is inserted. This trick in principle can mess up the replication of any RNA virus (not just SARS-nCoV-2), and in the test tube it did so for Ebola, SARS original edition ;), and MERS — but when given to actual Ebola patients its performance was underwhelming. (Such is the difference between a model and a patient.) Fortunately, it seems to be rather more successful against SARS-nCoV-2.

(2) In an earlier post, I looked at (meticulous and generally reliable) statistics for South Korea. At the time their case fatality rate (CFR) was only about 1%: according to a more recent Korean CDC report, it is 2.26%. Now their report gives a detailed distribution by age cohort. Apparently, their infections are not homogenously spread across the age pyramid: if we were to apply their mortality rates per age cohort to the published population pyramid of South Korea, we would get a CFR of 2.01%. If we substituted the much “younger” published population pyramid of Israel, that would lead to a CFR of 1.58%. This is still higher than the 1.35% I mentioned yesterday, but clearly indicates that the discrepancy between South Korean and Israeli CFRs is at least in part explicable by different age distributions.

(3) Miscellaneous updates:

• Via Instapundit, more evidence for a relationship between vitamin D deficiency and COVID19 mortality . A 2017 British Medical Journal paper shows the greater susceptibitlity of vitamin D-deficient people to respiratory infections in general: https://doi.org/10.1136/bmj.i6583 John Campbell has a point when he’s a bit of a “broken record” about vitamin D.
• Pulmonologist and medvlogger Roger Seheult MD about famotidine (Pepcid) as a potential COVID19 drug. Apparently the drug interferes with the viral protease. The ongoing trial has 1174 patients in 3 arms; (1) famotidine + hydroxychloroquine; (2) just hydroxychloroquine; (3) historical controls (who received neither).
• more serological data for the USA:

“I think it is the worst pandemic since 1918,” said Cecile Viboud, an epidemiologist at the National Institutes of Health’s Fogarty International Center, alluding to the “Great Influenza” pandemic that claimed an estimated 675,000 lives in the United States.

The new serological data, which is provisional, suggests that coronavirus infections greatly outnumber confirmed covid-19 cases, potentially by a factor of 10 or more. Many people experience mild symptoms or none at all, and never get the standard diagnostic test with a swab up the nose, so they’re missed in the official covid-19 case counts.

[…]A commonly cited statistic about seasonal flu is that it has a fatality rate of 0.1 percent, That, however, is a case fatality rate. The infection fatality rate for flu is perhaps only half that, Viboud said. Shaman estimated that it’s about one-quarter the case fatality rate.

• an article in Die Welt (in German) looks at the male-female mortality difference, which is most pronounced in the younger cohorts (the article speaks of 3:1 for people in they 50s) but dwindles to 1.5:1 in old age. Estrogen production in women is of course decreased in old age…

• Via Instapundit: confirming earlier Chinese hints, a preprint from New York Presbyterian Hospital reports a relatively small, but significant difference in COVID-19 suspectbility between Rhesus-positive blood groups. (The difference for Rhesus-negative ones is not statistically significant.) O is least suspectible, A most so. (Unlucky me ;))

• reports of reinfection of cured patients in South Korea appear to be due to false positives in testing: (h/t Instapundit). RT-PCR cannot tell non-viable virus fragments apart from “live” virus

• And via Sarah Hoyt, disinfectant poisonings in children are on the rises since the epidemic. Reportedly, call volume rose by 20%. What does that mean in absolute numbers? According to https://www.poison.org/poison-statistics-national in 2018 hotlines of the 55 U.S. poison control centers assisted 2.1 million callers with actual or suspected poison exposure. 44.2% of these calls concerned children younger than 6. So 20% of 44.2% of 2.1 million works out to… 15,470 calls per month. I suspect a large fraction of these calls concern toddlers who cannot stop themselves from taste-testing any possible and impossible household object — but in a population of 330 million people, by the law of large numbers you will find some derpseals who will actually think drinking household cleaners is a good idea. [**]

Speaking of which, whatever marketing “geniuses” thought THIS was an appropriate packaging for household cleaning fluid — it looks almost exactly like a grape-flavored soft drink that is wildly popular with toddlers here — need to have their head examined. Or maybe THEY’ve been drinking too many cleaning fluids.

[*] allow me to belabor this point: If we could reliably stop this disease from developing the severe presentation, we could afford changing gears entirely and allowing herd immunity to develop.

[**] I would caution against the automatic assumption that anybody who is mind-blowingly stupid in one thing is an idiot overall. I know many brilliant scientists and artists who couldn’t manage a grocery store, or a vegetables stand in a farmer’s market, to save their lives. One of the surprising things I learned from Jan Swofford’s excellent biography of Ludwig van Beethoven was that he would multiply numbers by repeated addition — he never learned how to multiply  properly.  (Beethoven had been groomed as a child prodigy keyboardist — his father, a washed-up court musician, harbored hopes of turning Beethoven into the next Mozart — so young Ludwig’s general education was perfunctory at best. Nevertheless, he  became an avid reader and was very familiar with the literature of his day, which inspired a number of his greatest compositions. Mozart’s general education was similarly defective. J. S. Bach actually graduated from a Latin high school — with indifferent grades, but three years younger than his class average — and later collected numerous scholarly works on theology, in Latin and in German, when he could afford to do so.)

COVID19 update, Yom HaAtzma’ut edition: “Coronahotels” for mild cases in Israel; pathology professor discusses what can be learned about COVID19 from autopsies

Happy Independence Day/Yom Atzmaut Sameach to my fellow citizens of Israel

(1) In the video below, you see an interview with IDF soldiers staffing a “CoronaHotel”. As our hotels are basically shutdown anyhow, the government requisitioned a number of them to create a third option for people not sick enough to need hospital care, yet whose living conditions do not permit safe home isolation (e.g., because they might infect family members or roommates): the “CoronaHotels”. 

These places are operated by (mostly female) IDF soldiers in their mandatory service: here is a video interview with one of them

No, the hotel is not on a dark, deserted highway 😉 — the one in the video is the Dan Panorama in Jerusalem, normally an upscale tourist and business hotel.

But can you check out? This is not in the hands of the IDF but of doctors, under the overall authority of the Health Ministry.

As I scraped together from different sources:

• if you tested positive but never showed symptoms, you get retested after two weeks, and if you are negative for the virus then you can go home. If you still test positive, you are retested a week or so later.
• If you did get a mild flu-like illness, you are tested after you get better.
• Of course, if your condition worsens, you are transferred to a hospital. In this manner, hospital beds are only used for COVID19 patients who actually need hospital care.

According to the latest Ministry of Health update, https://govextra.gov.il/ministry-of-health/corona/corona-virus/

1,726 people are currently in CoronaHotels, 4,540 mild or suspected cases are in home isolation, and just 352 people are in hospital. Of the latter, 120 are in grave condition (91 of them on artificial respiration), 85 in moderate condition,  and the remainder currently in mild condition (presumably convalescent after more severe episodes). 212 people have died, 7,929 have officially recovered. Out of 15,782 documented infections, that leaves 7,641 active cases, down from their peak of 9,808 on April 15.

(2) Moving from Israel to Germany, DIE WELT has a long (and for me enlightening!) interview with two pathologists at the U. Of Hannover medical school, one of them a lung pathology professor. They perform numerous autopsies on patients deceased from COVID19. Normally they spend 5% of their time doing autopsies and 95% analyzing tissue samples from living patients, mostly for suspected tumors or to help establish optimal cancer treatment plans for confirmed tumors. Nowadays — mostly COVID19 dead. Below follows a mixture of paraphrased summaries and (in quotation marks) hand-corrected machine translations from the original German.

The pathologists broadly hint that invasive respiration (“ventilators”) does more harm than good, and exposes the patients to all sorts of secondary infections [by antibiotic-resistant “hospital bugs”]. 

Primary infection is via nose and throat. 80% of cases are mild [and get better without treatment]. Of the remaining 20%, one-third end up in intensive care with severe lung involvement.

“Jonigk: Blood clotting occurs in the lung [capillaries], which are in the walls of the lung alveoli that serve to absorb oxygen and remove CO2. The damage causes protein to escape from the blood into the alveoli. Oxygen must somehow be transported from the air we breathe into the capillary network. That’s how we breathe. Anything that lengthens that route ensures that the patient can no longer supply himself with sufficient oxygen. It’s like playing soccer when you’ve skinned your knee: First a brown-red crust of protein and blood develops. We have a similar situation in the air bubbles. And breathing through them is massively difficult. The patient has a feeling of breathlessness, too little oxygen gets into the organism. It is more likely to be secondary to an inflammatory reaction. A downward spiral begins, which ends in a so-called shock lung. The lung and with it the patient fight for their lives.[…]”

Q: [which pre-existing conditions?]

A: “Older people with previous damage to the lungs. Patients who are dependent on medication that diminishes the immune system. And smokers, for example. Or people who live in an area with high particulate matter pollution and therefore already have pre-damaged lungs. So they are already not well before that. If an acute infection such as SARS-CoV-2 is then added, this can be enough to put the already sick patient’s life in danger.”

“Classic pneumonia is a bacterial infection with purulent sputum. The pus is yellow because it is made up of fatty granulocytes. Their task is to fight the enemy, the pathogen, in the body. But SARS-CoV-2 is a virus. It attacks cells directly and reprograms them. After an initial unspecific reaction, the response to this infection consists of specific T-lymphocytes, a subtype of white blood cells. These can recognize and attack virus-infected cells. We now have a large number of lymphocytes in the basic structure of the lung, which collect in the walls of the alveoli and develop their inflammatory activity there.”

Q: [what about other organs?]

“Up to 25 percent of intensive care patients have disorders of liver and kidney functions. In addition, blood coagulation often appears to be permanently disturbed. Small, local blood clots form at many sites because the inflammatory cells beat around to destroy the virus-infected cells, which include vascular cells. No matter where this occurs, it always has considerable consequences for the organ — strokes occur and sometimes extremities have to be amputated. In many organs, the occlusion of a blood vessel can be compensated. But if you have many occlusions, the blood does not flow properly, organ damage occurs, inflammatory cells do not get where they actually want to go, and the heart is also put under strain.”

Q: [is this just a COVID19-thing?]

“When you have a nasty cold with a fever, there’s always the recommendation: “Don’t go to the gym.” The basic idea behind this is that any virus can, in principle, infect any organ. Normally you have a resting heart rate of 65 or 70, but if you want to be a tough guy and go to the gym and treadmill and give it all you’ve got, you have a pulse of 150, so your heart is pumping properly. The chance of the virus infecting the heart suddenly increases dramatically. When you are infected, the body fights most viral infections with lymphocytes that go to the heart muscles and kill the infected cells. And this heart muscle inflammation is the most common reason for heart transplants in people under the age of 25.”

“At the moment when [the blood flow in] small vessels in the lungs is disturbed, the heart has to apply increased pressure to pump the blood through the lungs at all. This places an enormous strain on the right ventricle, which is normally only responsible for a low pressure. If the pressure requirements increase, it is quickly overtaxed, resulting in acute right heart failure. The left ventricle does not pump the blood into the lungs, but into the rest of the organism. It is capable of producing a pressure four to ten times greater than the pulmonary circulation. Regardless of whether it is caused by Covid or some other infection: as soon as the pressure in the pulmonary circulation is increased and the right heart is put under pressure, the patient can quickly die. […] So when the lungs are infected, the right heart has to run at full throttle for 1.5–2 weeks and is stressed far beyond normal levels. A young, fit person is more likely to cope with this than someone who already has a previous injury. But the virus is apparently also able to damage the heart itself. And the blood clots can of course also appear in vessels in the heart. So you have a heart that is pumping strongly, and suddenly the blood supply to the heart itself goes down. Then you have two hard strains, which can already be too much for the damaged heart.”

Q: [what about pre-existing conditions?]

“There is the old saying: A healthy patient is only a patient who has not been examined well enough. For example, high blood pressure is a classic disease of old age. In Germany, this will be about 35 percent of the total population. Up to now, mainly elderly people in Germany have died of Covid-19, which means that most Covid-19 deaths have had hypertension. Us being Germans, we also drink a lot of alcohol, so many citizens are overweight and have a fatty liver. The patient over 60 who has no previous illness – statistically there are only few. The important thing is not that there are pre-existing conditions, but which ones. And in what context do these have an influence on the probability of survival in the case of Covid-19 disease? It’s not enough to say, “This patient had something.” Rather, the previous illnesses must be systematically uncovered in relation to the population.”

“You have to separate whether someone died of, or with, a Covid-19 infection. It’s already affecting statistics. As far as we know, in Italy a corona test was carried out on every person who died and everyone who was found to have the virus was considered to have died of corona. In the case of pre-existing conditions, a distinction must also be made between diseases that generally shorten life expectancy and diseases that specifically increase the risk of corona infection and possible complications. This is somewhat muddled in the public discussion.”

Q: [brain involvement]
A [paraphrased]: we cannot conclusively rule out direct virus involvement, but the brain is so sensitive to disturbances in blood flow that blood clots quickly lead to headaches, then strokes.

[Paraphrased] “Overall, we know a lot about what happens at the cellular level with the virus, but relatively little about what happens at the organ level. Cell cultures can only tell you so much. So here is where autopsies come in.”

COVID19 update, April 28, 2020: drug repurposing; perverse incentives; Neil Ferguson now sees further lockdowns as impractical

(1) “Drug repurposing”: it’s a thing. Basically, if you have an emerging disease and need a remedy right this minute — even if you design a new drug that works well in the test tube, you are still faced with months of Phase 1, 2, and 3 clinical trials.

In contrast, if you can repurpose an existing drug that is already approved for treatment of another condition, you can skip testing whether the drug is safe, what side effects it has, and what is a safe dosage range. (As the old quip goes, nothing is safe at all doses, not even dihydrogen monoxide ;)) All you need to establish is: does it work against the new disease?

So there have been massive efforts to screen databases of approved drugs for molecules that inhibit this, that, or the other enzyme that is a vital part of the viral reproduction cycle. Increasingly, the first step of this is done on the computer, and the most promising candidates are then tested out in vitro, then in “animal models”.

But sometimes scientists stumble serendipitously on something that seems to work. SCIENCE magazine reports on… the H2 antagonist famotidine (sold in the US under the brand name Pepcid), used widely as a heartburn remedy until more recently displaced by proton pump inhibitors such as omeprazole (Prilosec).

“The virus was killing as many as one out of five patients older than 80 [in Wuhan]. Patients of all ages with hypertension and chronic obstructive pulmonary disease were faring poorly. Callahan and his Chinese colleagues got curious about why many of the survivors tended to be poor. “Why are these elderly peasants not dying?” he asks.

In reviewing 6212 COVID-19 patient records, the doctors noticed that many survivors had been suffering from chronic heartburn and were on famotidine rather than more-expensive omeprazole (Prilosec), the medicine of choice both in the United States and among wealthier Chinese. Hospitalized COVID-19 patients on famotidine appeared to be dying at a rate of about 14% compared with 27% for those not on the drug, although the analysis was crude and the result was not statistically significant.

But that was enough for Callahan to pursue the issue back home. […]

“Anecdotal evidence has encouraged the Northwell researchers. After speaking to Tracey, David Tuveson, director of the Cold Spring Harbor Laboratory Cancer Center, recommended famotidine to his 44-year-old sister, an engineer with New York City hospitals. She had tested positive for COVID-19 and developed a fever. Her lips became dark blue from hypoxia. She took her first megadose of oral famotidine on 28 March. The next morning, her fever broke and her oxygen saturation returned to a normal range. Five sick co-workers, including three with confirmed COVID-19, also showed dramatic improvements after taking over-the-counter versions of the drug, according a spreadsheet of case histories Tuveson shared with Science. Many COVID-19 patients recover with simple symptom-relieving medications, but Tuveson credits the heartburn drug. “I would say that was a penicillin effect,” he says.”

“After an email chain about Tuveson’s experience spread widely among doctors, Timothy Wang, head of gastroenterology at Columbia University Medical Center, saw more hints of famotidine’s promise in his own retrospective review of records from 1620 hospitalized COVID-19 patients. Last week, he shared the results with Tracey and Callahan, and he added them as a co-authors on a paper now under review at the Annals of Internal Medicine. All three researchers emphasize, though, that the real test is the trial now underway. “We still don’t know if it will work or not,” Tracey says.”

I am definitely looking forward to the results of that trial.

(2) I have heard the claim made that US hospitals have a financial incentive to code a patient as COVID19. Given the complexity of the US health insurance market (and governmental players in it), it struck me as “plausible, but verify”. Turns out: yes, Virginia. (The article notes that notoriously left-biased Snopes agrees with them.)

In our own system, there is no financial incentive to do so as it all comes out of the same insurance pool (divided among the four authorized HMOs by enrollment, not actual costs). Whatever downsides our socialized-with-private-options medical system may have, a perverse incentive to code a non-COVID19 patient as COVID19 is not one of them. As a result, we have “only” 208 COVID19 deceased at the time of writing, according to the Ministry of Health’s daily update.

A source in Belgium’s medical community told me that pathologists massively write COVID19 as the cause of death “if the patient has even been near a COVID19 case”, even if the actual cause is heart attack, stroke,… This appears to be one reason for the anomalously high per-capita COVID19 mortality in Belgium (the highest in the world, and far in excess of next-door Germany which uses much stricter criteria). When all-cause mortalities were compared year over year, an excess mortality was found that is comparable to neighboring countries.

(3) In this interview with Imperial College modeler Neil Ferguson https://www.youtube.com/watch?v=6cYjjEB3Ev8 (yes, the one with the “two million million will die” model, that later got revised drastically downward) he seems to take a more nuanced position than some of his acolytes, sees continued lockdown as unrealistic “and causing excess mortality from other causes” (!), expects a second wave (he’s not alone in that), and favors a South Korean-style test, track & trace approach. Defends himself as “as a nation, we acted in time to prevent a breakdown of medical services”. For balance, I offer a video on the same channel by his Swedish critic Prof. Johan Giesecke. https://www.youtube.com/watch?v=bfN2JWifLCY The interviewer is fairly tough on both: nice to see some actual journalism.

(4) in John Campbell’s daily update, https://www.youtube.com/watch?v=lu00u2dEnbs about 16 minutes in, John Campbell discussed “pediatric inflammation syndrome” in the UK. Is it COVID19 or some unidentified viral pathogen? Abdominal pain, GI symptoms more annoying than anything else, cardiac involvement more worrisome. “Let’s hope that comes to nothing, but would seem to be expedient to have a higher index of suspicion [of abdominal pain in children].”

He also thinks Canada is starting to look good.

(5) Miscellaneous updates (h/t Mrs. Arbel):

• pathologists are reshaping the time line of when the virus arrived to the USA. https://www.wsj.com/articles/pathologists-hunt-for-earlier-coronavirus-cases-in-new-york-11588003955 For instance, in early February, a 57-year old woman in Santa Clara County, CA (read: Silicon Valley) died of what later found to be COVID-19. [Note that, since it takes 2-3 weeks to get sick enough to die of the virus, that implies she was infected around mid-January.]

• The secretive group of scientists and billionaires pushing for a Manhattan Project against COVID19 (which would not be specific to SARS-nCoV-2 but likely cover the entires family of coronaviruses) https://www.wsj.com/articles/the-secret-group-of-scientists-and-billionaires-pushing-trump-on-a-covid-19-plan-11587998993?mod=trending_now_1
• Israel Aircraft Industries proposes UV-C based “sterilization robot” for passenger airplanes. This technique is both more effective than disinfectant fluids, works faster, and does not require “drying time” after treatment.  https://www.jpost.com/israel-news/israels-iai-tests-uv-light-solution-to-sterilize-passenger-aircraft-625983

Today, Israel marks Yom HaZikaron, or Memorial Day, for its fallen soldiers. Tonight (days on the Jewish calendar run sundown to sundown) it will transition into Yom HaAtzmaut or Independence Day — the former to remind us of those who paid the ultimate price for the latter.

COVID19 update, April 27, 2020: Israel and Europe progress; worrisome signs in the US food supply chain; Bastiat and “non-urgent” healthcare

(1) Let’s have a quick roundup of the latest active cases data from worldometers (I’ll leave Israel to the last):

Germany’s active cases 39,794 are down to 55% of the peak value on April 4, 72,865. Switzerland is doing better still — 5,651 down from a peak of 14349 on March 31, or down to 39% of peak. Austria stands at 2,401, or down to 26% of its April 3 peak of 9,334. Norway’s graph has no info on recoveries (hence no useful info on active cases), but daily new cases are a fraction of their peak. Total dead are clearly nearing the top of the sigmoid at 201. Finland’s graph looks like a wild zigzag owing to intermittent reporting of recoveries — but seems to be trending the right way. Active case graphs in Spain, Italy, and France seem to indicate these countries are turning the corner — if they can prevent a second flare-up.

Belgium, however, is not out of the woods yet, nor are the Netherlands and the UK. Sweden looks murky, with active case numbers still climbing about linearly, but total deaths seemingly starting to level off. The US — overall looks pretty grim still, but if greater New York City were taking out of the equation, the rest of the country looks rather rosier.

As for Israel: our active cases have been dropping steadily since April 15, from a high of 9,808 to the present 8,511. Recoveries have exceeded new cases since April 16. The total number of dead has crossed the 200 mark, but the curve over time shows a clear sigmoid that appears to be close to leveling off. With 15,443 documented infections since the beginning of the crisis (of which 6,731 documented recoveries), our apparent “case fatality rate”, at 201/15,443*100% = 1.3%. However, keep in mind that Israel counts everybody who tests positive, whether they develop symptoms or not. Guesstimating about half of these to be asymptomatic, the true CFR may be closer to double that, while the true IFR (infection fatality rate) is certainly lower than 1.3%, as despite increased testing capability the country is sure to have a significant Dunkelziffer/stealth infection rate. (Do keep in mind Israel has a much younger population pyramid than the major developed countries — this alone accounts for our low number of severe cases. The stories of young and healthy people without pre-existing conditions getting severe COVID19 are “man bites dog” news, not significant shares of the patient population.)

Israel indeed has done something today that I can only hope the US is wise to do soonest: opened its hospitals and HMO policlinics for elective procedures. (A lot of “gray area” care is technically elective in that it doesn’t have to happen right this second — but any unnecessary delay will cause complications later.)

Finally, in India lockdown is to end May 3, but it’s getting rolled back already in some less-stricken locations.

(2) Rather more worrisome news from the US, with twin posts (here and here) reporting about food supply chain disruptions from the agricultural side of things. I reached out to a few people informed about goings-on, and the problems are basically threefold:

• Choke points in the distribution chain were created by COVID19 outbreaks at meat processing plants (like Smithfield’s in South Dakota), which necessitated closure, sanitation, and reopening at reduced capacity. (At some processing plants, workers are also reluctant to show up.) Hence, farmers are stuck with hogs etc. and no place to have them processed.
• Farmers whose chief outlet was to the large food service companies and institutional customers are now stuck with product they cannot unload, except at a loss. Their operational cash headroom is limited at the best of times;
• Meanwhile, those who supply to the grocery chains see shifting demand. Dairy, for instance, is down. This has caused prices paid to farmers to drop to “below cost” levels.

There are second-order effects: corn growers who primarily supply pig farmers etc… And with oil prices down to historical lows, selling corn for ethanol is not practical. (Incidentally, while some farmer supplies (e.g., fuel) are cheaper, others go up in price because imported from, you guessed it…)

I doubt dire predictions of famine in the USA will come to pass (and dearly hope and pray they won’t). However, remember the USA is a major food exporter — and that it is likely to apply the maxim “the poor of my own city come first” in a serious food crisis. So major shortages in countries that are dependent on US food imports are increasingly likely. 

“Just-in-time” supply chains can normally respond smoothly to ordinary shifts in demand, and thus keep prices down for the end consumer. However, they are fragile to major disruptive events like COVID19. The old engineer’s maxim “better, cheaper, faster — pick any two” seems to have a supply chain counterpart: “cheap, just in time, robust: pick any two”. 

The social distancing measures in the USA (outside greater NYC,  and perhaps a few other congested metropolitan areas) have crossed the line from diminishing returns territory into doing more damage than they prevent — it is high time to return no normality. Scott Atlas MD definitely agrees.

(3) On a final note: Dr. Paul Hsieh quotes Bastiat about “the seen vs. the unseen [costs]” in the context of emergency care. (Bastiat’s classic essay expounding the concept of hidden costs and consequences should be required reading, not just for any economics student, but for every public servant and every elected official.) The number of COVID-19 deaths are in the public eye. The number of people dying from cardiac complications or ruptured appendicitis because they were unwilling to come to the ER for fear of contracting COVID19 (a phenomenon seen in Europe as well as the US) are not so obvious — but they are still there. This is without going into the urgency level one step below: cancer surgeries, non-emergency bypass surgeries,…

UPDATE: John Tyson, chairman of the board of Tyson Foods, weighs in on the company’s blog: “Feeding the nation and keeping our employees healthy”.

UPDATE 2: more about the MIT study on the NYC subway as “the mother of all super-spreader events”.

COVID19 update, April 26, 2020: NYC vs. rest of USA; super-spreader events analyzed; reopening non-emergency care; cyclic lockdowns

(1) Bret Stephens in the NYT: lockdowns are good for NYC, but why should the rest of the USA have to play by the same rules as congested NYC?

https://www.nytimes.com/2020/04/24/opinion/coronavirus-lockdown.html?referringSource=articleShare (archive version http://archive.vn/uCqD7) 

As of Friday, there have been more Covid-19 fatalities on Long Island’s Nassau County (population 1.4 million) than in all of California (population 40 million). There have been more fatalities in Westchester County (989) than in Texas (611). The number of Covid deaths per 100,000 residents in New York City (132) is more than 16 times what it is in America’s next largest city, Los Angeles (8). If New York City proper were a state, it would have suffered more fatalities than 41 other states combined.

It isn’t hard to guess why. New York has, by far, the highest population density in the U.S. among cities of 100,000 or more. Commuters crowd trains, office workers crowd elevators, diners crowd restaurants. No other American city has the same kind of jammed pedestrian life as New York — Times Square alone gets 40 million visitors a year — or as many residents packed into high-rises. The city even has a neighborhood called Corona, which, it turns out, has among the highest rates of coronavirus infections.

Consider a thought experiment in which metropolitan New York weren’t just its own state, but its own country. What would the crisis for what remained of America look like, then? In this slightly smaller nation of a little more than 300 million people, the death toll would amount to about 7.5 per 100,000, slightly above Germany’s levels.

I also suspect that, if NYC were at the same latitude as Miami or Houston, it would have seen much lower mortality even with the same population density. Although the NYC subway still strikes me as “the mother of all super-spreaders”, and a study from MIT agrees.

(2) Speaking of super-spreader events: Quillette’s Canadian editor Jonathan Kay did some research of his own into 38 such events in 28 countries. (He restricted himself to documented events in languages he could read: the Purim super-spreader events in Israel he therefore dismissed, despite the extensive documentation I have seen in the Hebrew-language press and social media.) At any rate, let me (over?)summarize some of the patterns seen over and over:

• mass events (at high density), not people going about normal day-to-day business (unless said business involves catering at crowded mass events, of course)
• long duration
• extremely close physical contact — kissing, hugging, or shouting into people’s faces or ears (e.g., because the music at the event was so loud).

Buying seeds or “nonessential” household items is not on this list, needless to say. (If of course said purchase requires queueing in tight quarters for hours, that’s another matter.)

(3) Rick Jackson, chairman and CEO of Jackson Healthcare, the 3rd largest health care staffing company in the USA, points out in an op-ed in Newsweek [!] that many hospitals are standing empty and face closure unless allowed to treat “non-urgent” non-COVID19 patients again — and urges authorities to permit this. He points out that no fewer than 1 in 8 [working] Americans work in healthcare…

(4) The group of systems biologist Uri Alon at the Weizmann Institute developed this “Adaptive cyclic exit strategies” simulator  http://cyclic-strategy.herokuapp.com

Their idea in a nutshell: work x days on, y days off (their recommendation is x=4 and y=10), for example by alternating shifts. I think the easiest to implement in practice would be x=5 and y=9, two shifts (i.e., alternating working weeks). The 9-10 days at home would mean anybody who got infected at work would either be showing symptoms or asymptomatically test positive by the time they’d have to go back to work.

View at Medium.com

Their simulations show that this is a way to achieve most of the benefit of a full lockdown, while still permitting about 50% economic activity in non-telecommutable sectors (so probably 70%+ overall).  The active case load, rather than a monotonic decay as in a full lockdown, would get a damped oscillation superimposed on it. Below is an example:

Anyway, have a look at the simulator. The key is to keep the effective reproductive number Rt (in their notation) below 1 so the epidemic will die out eventually. A number of larger Israeli companies have adopted this strategy, with two staggered shifts.

(5) As a final reflection: the more I think about COVID19, the more it sounds that, if we had a reliable way to prevent cytokine storm, or nip it in the bud if it appears, we would be following a drastically different strategy. I talked to a source in the drug design community, and it sounds like more and more immunosuppressant/immunomodulator drugs are being repurposed for clinical trials (or compassionate use) in severe COVID19.

COVID19 update, April 25, 2020: doctor videos edition

Good morning, happy weekend, shabbat shalom. In today’s update, mostly videos, which I’m linking rather than embedding (as a workaround for a WordPress dot com editor bug).

(1) Mike Hansen MD reviews COVID19 drug trials. He’s bearish on HOcq (2/10) but surprisingly bullish on ARBs (angiotensin II receptor blockers, 7/10) and to a lesser extent ACE inhibitors (5/10), both types of drugs in established use as antihypertensives. For remdesivir: great results in Chicago leaked, less so in Mass (7/10). Favipiravir [sold in Japan as AVIGAN as an anti-influenza drug] targets RdRp (6/10). IL-6 inhibitors:  tocilizumab (approved for managing cytokine storm, used in severe RA and in immunotherapy complications): expensive, potent immunosuppressants (5/10).  

His top 5: Recombinant ACE2 (8/10); ARBs tied with remdesivir (7/10) and favipiravir/Avigan (7/10); Umifenovir/Arbidol (6/10)

(2) Via reader Dawn Miller, a two-part interview by a local ABC affiliate with Dr. Dan Erickson, operator and chief physician of Accelerated Urgent Care in Bakersfield, CA. Among many other things, he is saying that, at least at this point, the lockdown in CA is doing much more harm than the disease itself.

• Part 1 (bulk of the interview)
• Part 2 (Q&A segment after length limit reached)

On a tangentially related note, a medical source in Belgium told me that, while they never did the “shut everything down to make room for COVID19 patients” thing, they notice a steep drop in patients coming in with suspected cardiovascular and cerebrovascular complaints, and like their German colleagues, they can’t believe “heart attacks and strokes are suddenly 30% less frequent”. They believe they’ll have huge “medical cleanup bills” on deferred care cases. He also told me that in the grey area of urgency, access to care can be problematic: he gave the concrete example of a tooth abscess in an elderly patient with a pacemaker. As pericarditis is a not-uncommon complication of dental surgery in such “risk patients”, he referred the octogenarian to an oral surgeon at the local hospital — but the department was closed due to COVID19. “Just take antibiotics.”

(4) Miscellanea:

• U. of Washington doing new hydroxychloroquine trial, but now seeing if it can stop mild cases from becoming severe;
• (h/t: Erik Wingren) fatal strokes showing up in young coronavirus patients?! (WaPo; archive) We know (see, e.g., Dr. Seheult’s video I’ve been linking) that blood clotting in the lungs is one phenomenon occurring during severe COVID19, hence prophylaxis regimes of some doctors include mild anticoagulants/antithrombotics like low(ish)-dose aspirin. Note that at least here, many doctors start prescribing the latter to patients for cardio- and cerebrovascular prophylaxis when the patients reach their fifties: these younger patients would not yet have been on them.
• Marc Andreessen  [of Mosaic/Netscape fame, and now Andreessen Horowitz]: It’s Time To Build
• Belgium update: politicians accelerate the unlock time table, reports De Standaard (in Dutch): the 2nd phase has been moved from May 18 to May 11.
• A community immunity testing effort by the University of Geneva Hospital is reported on here (in French). More later perhaps on this, but as of April 17, they found that 5.5% of testing subjects had antibodies for COVID19. Again we see a very substantial Dunkelziffer/”dark number”/stealth infection rate: on the same day, total known COVID19 cases accounted for just 0.3% of the Swiss population, though I don’t have numbers for Geneva specifically.
• DIE WELT (in German) reports on the situation in the mostly-immigrant Paris suburbs of the 93rd Département, where workers in both the formal and “informal” economies have been pushed out of work. Even the Préfect (chief administrator of a Département, somwhere between a County Judge and a Governor in US parlance) takes seriously the possibility of food riots.

UPDATE: via David S. Bernstein, a profile of Stanford statistician John Ioannides (WSJ behind paywall, archive copy here).

COVID19 update, April 24, 2020: Belgium reopening May 4, Israel reopens “phase 1.5”, NYC immunity testing, nicotine

(1) Belgium has been nibbling around the edges of its existing lockdown, allowing phone stores, garden stores, etc. to reopen, but (with the highest per capita COVID19 mortality of any country in the world) experts kept saying they were not out of the woods yet. Now the country’s national security council decided on reopening in two phases, May 4 and May 19. https://www.standaard.be/cnt/dmf20200423_04932921

In Phase 1 (May 4), the following will again be permitted:

• outdoor sports like tennis, angling, horseback riding (as a family, or in pairs — not yet in group)
• registered sports teams can resume training
• public parks etc are reopened
• car dealers/garages, bike shops, real estate offices may function “by appointment” (not yet walk-in)
• smaller home improvement shops (paint, tiles, lighting fixtures, kitchen stores,…) may reopen
• non-essential enterprises may resume activity, subject to social distancing
• masks will be mandatory on public transit. (Belgium has an extensive multimodal network.)

Phase 2 (May 18) adds:

• all remaining businesses may reopen. Hairdressers have to wear masks
• schools gradually reopen
• museums reopen for individuals or families, not yet for groups
• meetings up to 50 permitted
• visit to vacation homes (in practice, on the sea coast or in the Ardennes): details to be finalized

“Horeca” (hotels, restaurants, and cafés) are not to be opened before June 8.

(2) Israel was supposed to have its Phase 2 reopening in a week, but apparently decided to speed things along a bit. As of Sunday, remaining stores are allowed to reopen. In addition, hairdressers are allowed to reopen, with maximum 2 clients at a time, and disinfecting equipment between every haircut. Indoor malls still remain closed for now. Restaurants, which until now were only allowed to operate by delivery, are now also permitted to offer takeaway (not yet with seating).

The country will go in hard lockdown over Memorial Day and Independence Day, to prevent super-spreader events like there were at Purim, but that should be “it” for a while. Active COVID19 cases in Israel have been declining for a week now, as recoveries outpace new cases.

(3) Much ado about preliminary results from a community testing effort in NYC that appears to indicate as much as 20% of the NYC population has antibodies for COVID19. (The figure drops to 3.6% for upstate New York.)

(4) (Hat tip: Erik Wingren.) Peculiar and counterintuitive claims (see here and here) from France that smoking, and specifically nicotine, would have a protective effect — specifically, that the COVID19 patient populations contained an anomalously low percentage of smokers compared to the general population.

A French study from the Université Pierre et Marie Curie found that just 8.5 percent of 11,000 hospitalized coronavirus patients were smokers compared to 25.4 percent of the country’s population.

They are now experimenting with nicotine[*] patches. The initial data from China (caveat emptor) appeared to indicate that smoking was a risk factor because of damage to the lungs — but that damage comes overwhelmingly from tar, not from nicotine. (I wonder if anybody looked at “vapers” for comparison?) Anecdotally, a friend who is immunocompromised following an organ transplant, and has been having regular troubles with bronchitis, told me he took up vaping (which gives him nicotine but not tar), and it greatly reduced his respiratory issues.

[*] What is the purpose of nicotine in nature? Some plants produce alkaloids to deter animals from eating them: for this purpose, tobacco produces nicotine (named after Jean Nicot, the 16th century French diplomat who was the first to bring tobacco to France).

COVID19 update, April 23, 2020: community immunity testing results from Belgium; non-COVID19 hospital care; India

(1) DE STANDAARD (in Dutch) reports on a new immunity study in Belgium. Researchers from the University of Antwerp collected residual blood samples of 3,686 patients that had originally been taken for other purposes (e.g., to check for anemia) and checked those for COVID19 antibodies. The samples were collected on March 30.

The Antverpian team found that about 3% of the samples had antibodies — if their sample were truly representative, that would imply about 300,000 people had antibodies for COVID19 around March 30. 

Let’s work with this a bit, shall we? According to worldometers, on that date (March 30) Belgium had 11,899 documented cases. This implies a Dunkelziffer/“dark number” (De Standaard uses this English term) to documented cases ratio of about 25:1.

As of April 22, Belgium had 41,889 documented cases — if we (dubiously) assume that the “dark number” ratio is constant, then about 10.6% of the population may have antibodies at present. 

How much would you need for herd immunity? The herd immunity threshold %HI depends in a very simple way on the effective reproductive number R of the virus: 

%HI = 100% * (1 – 1/R)

If R≤1 then the epidemic will die out anyway and %HI is zero. For R=1.1 just 9% would already be enough, while for R0=1.5 you’d need 33%, for R=2 you’d need 50%, and for R=2.5 you’d need 60%.  (Corollary: if Belgium does have about 10-11% with antibodies, it doesn’t need to keep R below 1.0 with social distancing measures, but can let things slide a little higher. As the percentage of immune residents grows, further relaxation is possible.)

(2) At Sarah Hoyt’s blog, a guest post by “Scarlett Doc” called “Healthcare Charlie Foxtrot” about the current situation in US hospitals for non-COVID19 care. These are the fruits of rigid edicts by domineering, not-too-bright bureaucrats: entire hospitals sitting on their hands waiting for the COVID19storm to hit (which is largely confined to NYC and a few other hotspots), while myriad non-COVID19 patients go untended. There are even hospitals furloughing most of their medical staff. The article is aptly illustrated with a picture of a dumpster fire. Read and weep.

It gets bad enough even without meddlesome middlebrow bureaucrats with Messiah complexes. German hospitals by and large continued normal operations. Yet DIE WELT (in German) reports on how internal medicine wards in German hospitals see such a drop in admissions for their “big 3” emergencies (heart attacks, strokes, and appendicitis) that it is making doctors suspicious. https://www.welt.de/vermischtes/article207436223/Corona-Deutlich-weniger-Patienten-in-der-Kardiologie-Aerzte-werden-stutzig.html 

“It cannot be that we suddenly have 30% fewer strokes than usual because of corona” says one — so they suspect patients are staying away when they shouldn’t, out of fear of contracting COVID19. “In 2018 there were 210,000 heart attacks and about 300,000 strokes in Germany. That these numbers have suddenly contracted because of the Corona-epidemic, nobody in the medical community believes.”

(3) (Hat tip: Alex W.) Quartz India wonders why the remarkably low toll in India. A young population pyramid is a plus, but against that stand two minuses: multigenerational families and high incidence of chronic diseases even among fairly young people. Then again, the weather being very hot and humid (bad for the virus), universal BCG vaccination, and broad (hydroxy)chloroquine use in areas where malaria is endemic could all be factors. (Incidentally, monsoon season in India is flu season there, so we could see a surge then.)

Related, however, a recent preprint claims that the BCG differential is “an illusion created by testing”: https://www.medrxiv.org/content/10.1101/2020.04.18.20071142v1

(4) Finally, could the serine protease nafamostat (an anticoagulant that also has some antiviral properties) be a drug candidate for COVID19? A Japanese group shows in vitro evidence in this preprint: https://www.biorxiv.org/content/10.1101/2020.04.22.054981v1

UPDATE: Matt Ridley, popular science writer and member of the House of Lords, gives a layman-friendly overview of COVID19 drug candidates in the special 10,000th issue of The Spectator.

COVID19 update, April 22, 2020: the two faces of the disease, as explained by a pulmonologist; IL-6 and estrogen explaining gender differences?

(1) I saw a video by pulmonologist Mike Hansen MD that made me go “aha!”. He may be pitching its message a bit too strongly, but was delivered in a highly entertaining manner, and is easy to follow if you have some basic medical knowledge. See the video here. (Something is broken with the YouTube embedding widget that makes WordPress glacially slow to edit on my computer.)

It is almost like the disease has two faces. In the vast majority of patients, there is no involvement of the lower respiratory tract — just upper respiratory and some gastro-intestinal involvement (there are ACE2 receptors there), rarely some cerebral. This disease picture is the (generally) nonlethal one, ranging in severity from mild cold to severe flu without secondary infection. Such patients will get better on their own with nothing more than standard supportive treatment, like you would for a nasty flu at home.

It’s when the infection goes down to the lower part of your lungs that all hell can break loose. Effectively, the inflammation of the alveoli sets off a chain reaction (which he explains in great detail) that can easily blow up into ARDS (acute respiratory distress syndrome) and cytokine storm, and ends up with the patient getting killed by his own immune system. The key is to intervene before this happens.

In his picture, antiviral drugs would be most useful in the early stages — to stop the infection from spreading to the lower lungs — or even for prophylaxis. (However, I’d point out that, especially with remdesivir, there have been “saves” of severely ill patients.) In later stages of the disease, immunosuppressants actually would be more valuable, to rein in the immune system running amok.

The people who say “it’s just a flu” are actually right in 90+% of symptomatic cases. In the remainder it’s almost like what my brother would call the “autoimmune disease from Hell”.

Two other nuggets from the video:

(2) John Campbell keeps coming back to vitamin D and its vital role in the immune system. He points out that, while only 14% of Britons are nonwhite, they constitute nearly one-third of critical COVID19 cases. Socio-economic and cultural factors (e.g., multigenerational families under one roof, like is common in Italy) aside, vitamin D deficiency is much more common at northern latitudes if you have a dark skin type. (Anecdotally, I know that a family acquaintance of Yemenite-Jewish heritage [and hence with very dark skin] who moved to Sweden suffered all sorts of health problems, until UV lamps and vitamin D supplements entered the picture.[*] ) This aspect of the problem is very easy to solve…

Dr. Campbell is a bit dismissive of the estrogen-IL6 hypothesis “since why would there then be a gender difference at post-menopausal age?” Instead, he points out that many immunity-related genes are on the X chromosome, and if you have one defective copy and you’re male, that’s your only copy, while a female would have the 2nd X chromosome… (This is aside from the risk factor of smoking — in countries like China much more prevalent in men than in women.)

In another video (h/t Mrs. Arbel), he backtracks on earlier comments about Greece, and notes they have been more proactive than he thought (canceling school 9 days before the UK, in fact) and are now seeing the fruits thereof, as cases have dwindled. A similar decrease in deaths will lag by several weeks.

(3) Chemical and Engineering News, the house organ of the American Chemical Society, looks at the challenges for Gilead Sciences in scaling up production of remdesivir to the millions of doses range. In the earlier case of Tamiflu, Hoffmann-LaRoche licensed manufacturing from Gilead Sciences — and was able to provide 200 million courses’ worth of Tamiflu in comparatively short order.

(4) Via Instapundit: is there a correlation between universal BCG (Calmette-Guérin) tuberculosis vaccination policy and reduced COVID19 mortality?

(See also https://www.medrxiv.org/content/10.1101/2020.03.24.20042937v1)

I found this database of global BCG policies www.bcgatlas.org (documented here). Let me show a map:

A (ochre) refers to countries with mandatory BCG vaccination, B (purple) to countries who had it as mandatory in the past, and C (orange-red) to countries where it was never mandatory. The blatant difference in mortality between (culturally and ethnically very similar) Portugal and Spain has been ascribed to me by a Portuguese US immigrant to the existence of a parallel private medical system “that actually functions”, unlike the government-only option in Spain; but I wonder whether BCG couldn’t play a role. (TB used to be endemic in Portugal.) Belgium vs. Germany (again, ethnically and culturally quite similar) is another case. However, what about France then?

Israel used to have mandatory BCG until 1982—which implies the older generation (the most at-risk) would see some benefits. (As vaccines go, BCG is a pretty blunt instrument that “trains” the first responders of the immune system, which are not terribly selective.) And indeed, in combination with our young-ish population pyramid and our warm climate (today the mercury hit 90°F), this may go some way towards explaining the comparatively low mortality in Israel.

(5) The NYT has (in part with political ulterior motives) been cheerleading extended lockdowns, so I was surprised to see this article there on the collateral damage of shutting down all “non-emergency” activity at hospitals while bracing for a COVID19 flood. (Archived copy here.)

[…] Early on, as the epidemic loomed, many hospitals took the common-sense step of halting elective surgery. Knee replacements, face lifts and most hernias could wait. So could checkups and routine mammograms.

But some conditions fall into a gray zone of medical risk. While they may not be emergencies, many of these illnesses could become life threatening, or if not quickly treated, leave the patient with permanent disability. Doctors and patients alike are confronted with a worrisome future: How long is too long to postpone medical care or treatment?

Delaying treatment is especially disturbing for people with cancer, in no small part because it seems to contradict years of public health messages urging everyone to find the disease early and treat it as soon as possible. Doctors say they are trying to provide only the most urgently needed cancer care in clinics or hospitals, not just to conserve resources but also to protect cancer patients, who have high odds of becoming severely ill if they contract the coronavirus.

Nearly one in four cancer patients reported delays in their care because of the pandemic, including access to in-person appointments, imaging, surgery and other services, according to a recent survey by the American Cancer Society’s Cancer Action Network.

Tzvia Bader, who leads the company TrialJectory, which helps cancer patients find clinical trials, said frightened patients had been calling to ask her advice about postponements in their treatment.

One woman had undergone surgery for melanoma that had spread to her liver, and was due to begin immunotherapy, but was told it would be delayed for an unknown length of time.

“She says, ‘What’s going to happen to me?’” Ms. Bader said. “This is not improving her chances.”

And some clinical trials, where cancer patients can receive innovative therapies, have been suspended.

“The mortality of cancer has been declining over the last few years, and I’m so terrified we are going backwards,” Ms. Bader said.

[*] As for me, I can’t be outside for more than 30 minutes or so on an Israeli summer day without nasty sunburn 😉 There is a reason the term “redneck” exists in the American South, as does “rooinek” in Afrikaans…

COVID19 update, April 21, 2020: Colchicine; more on COVID19-related pneumonia and “stealth hypoxia”; community testing in Los Angeles; Belgium as seen from Germany

(1) Via Mrs. Arbel, here is info on a clinical trial of the ancient-as-dirt drug colchicine. This has been in use since Antiquity for the treatment of gout (full disclosure: I have been taking it for a while, when a low-carb, high-protein diet intended to lose weight gave me a painful bout of this “rich man’s disease”): this clinical trial investigates whether its early administration to COVID19 patients may prevent “cytokine storm”. (More here at Physician’s Weekly) https://www.physiciansweekly.com/anti-inflammatory-drug-colchicine-on-deck-for-covid-19/

I am wondering more than ever whether the vast majority of dead from COVID19 aren’t killed by the patients’ own immune systems going amok. (This was what caused most deaths during the 1918 “Spanish” Flu: the main difference with the present epidemic — other than the causative agent which was an influenza virus then, a coronavirus now — is that in COVID19 the severe disease picture seems to be the exception rather than the rule, statistically speaking.

How rare? Consider Israel, which tests reasonably broadly and is conservative about diagnoses, albeit admittedly has a “younger” population pyramid than most Western countries. The screenshot below is from the daily report by its Ministry of Health: https://govextra.gov.il/ministry-of-health/corona/corona-virus/  

As of the time of writing, we have 13,883 verified cases (read: people testing positive for the virus): 9,072 of them in mild condition, 135 in moderate condition, just 142 in severe condition of which 113 on respirators, 181 deceased (of course, 181 too many), and 4,353 verified recoveries — defined here as previously diagnosed, now without symptoms and testing negative for the virus. (The “170” at the top of the graph are new cases added.) Moderate+severe+dead together is 4% (four percent) of the total infected. (Probably closer to 8% or 10% of symptomatic/overt cases — since anecdotally, it seems that about half of Israel’s verified “cases” [read: verified infections] are completely asymptomatic.)

(2) “masgramondou” Emailed me this one from the NYT (original link: https://www.nytimes.com/2020/04/20/opinion/coronavirus-testing-pneumonia.html?action=click&module=Opinion&pgtype=Homepage archived here http://archive.is/QSBfc) in which an emergency physician named Richard Levitan MD at Bellevue Hospital in NYC talks about “stealth hypoxia” in COVID19 patients. Unlike the usual fodder at the NYT, this is a factual report with no obvious political axe to grind. Some moneygrafs:

And here is what really surprised us: These patients did not report any sensation of breathing problems, even though their chest X-rays showed diffuse pneumonia and their oxygen was below normal. How could this be?

We are just beginning to recognize that Covid pneumonia initially causes a form of oxygen deprivation we call “silent hypoxia” — “silent” because of its insidious, hard-to-detect nature.

Pneumonia is an infection of the lungs in which the air sacs fill with fluid or pus. Normally, patients develop chest discomfort, pain with breathing and other breathing problems. But when Covid pneumonia first strikes, patients don’t feel short of breath, even as their oxygen levels fall. And by the time they do, they have alarmingly low oxygen levels and moderate-to-severe pneumonia (as seen on chest X-rays). Normal oxygen saturation for most persons at sea level is 94 percent to 100 percent; Covid pneumonia patients I saw had oxygen saturations as low as 50 percent.

[…]

A vast majority of Covid pneumonia patients I met had remarkably low oxygen saturations at triage — seemingly incompatible with life — but they were using their cellphones as we put them on monitors. Although breathing fast, they had relatively minimal apparent distress, despite dangerously low oxygen levels and terrible pneumonia on chest X-rays.

We are only just beginning to understand why this is so. The coronavirus attacks lung cells that make surfactant. This substance helps keep the air sacs in the lungs stay open between breaths and is critical to normal lung function. As the inflammation from Covid pneumonia starts, it causes the air sacs to collapse, and oxygen levels fall. Yet the lungs initially remain “compliant,” not yet stiff or heavy with fluid. This means patients can still expel carbon dioxide — and without a buildup of carbon dioxide, patients do not feel short of breath.

Patients compensate for the low oxygen in their blood by breathing faster and deeper — and this happens without their realizing it. This silent hypoxia, and the patient’s physiological response to it, causes even more inflammation and more air sacs to collapse, and the pneumonia worsens until their oxygen levels plummet. In effect, the patient is injuring their own lungs by breathing harder and harder. Twenty percent of Covid pneumonia patients then go on to a second and deadlier phase of lung injury. Fluid builds up and the lungs become stiff, carbon dioxide rises, and patients develop acute respiratory failure.

By the time patients have noticeable trouble breathing and present to the hospital with dangerously low oxygen levels, many will ultimately require a ventilator.

Silent hypoxia progressing rapidly to respiratory failure explains cases of Covid-19 patients dying suddenly after not feeling short of breath. (It appears that most Covid-19 patients experience relatively mild symptoms and get over the illness in a week or two without treatment.)

And then the best part!

There is a way we could identify more patients who have Covid pneumonia sooner and treat them more effectively — and it would not require waiting for a coronavirus test at a hospital or doctor’s office. It requires detecting silent hypoxia early through a common medical device that can be purchased without a prescription at most pharmacies: a pulse oximeter.

Pulse oximetry is no more complicated than using a thermometer. These small devices turn on with one button and are placed on a fingertip. In a few seconds, two numbers are displayed: oxygen saturation and pulse rate. Pulse oximeters are extremely reliable in detecting oxygenation problems and elevated heart rates.

Pulse oximeters helped save the lives of two emergency physicians I know, alerting them early on to the need for treatment. When they noticed their oxygen levels declining, both went to the hospital and recovered (though one waited longer and required more treatment). Detection of hypoxia, early treatment and close monitoring apparently also worked for Boris Johnson, the British prime minister.

Widespread pulse oximetry screening for Covid pneumonia — whether people check themselves on home devices or go to clinics or doctors’ offices — could provide an early warning system for the kinds of breathing problems associated with Covid pneumonia.

Read the whole thing.

(3) (via Instapundit) KTLA reports on a new community antibody study in Los Angeles County https://ktla.com/news/local-news/l-a-county-officials-to-provide-latest-update-on-coronavirus-crisis/?fbclid=IwAR3ItNdY_00D6FkDjQRn-x5rK71A2XqLg-xgvPQFSN0YfI9batMXXNA6-s0  which corroborates various earlier reports that the USA, at least, may have a very significant Dunkelziffer/“stealth infection rate”.

While Los Angeles County has reported a total of 13,816 coronavirus cases, early results from an antibody study conducted with the University of Southern California shows that hundreds of thousands more could have had COVID-19 in the past, officials announced Monday.

So far, 863 L.A. County residents have been tested between April 10 and 14 as part of the study.

The study estimates a prevalence of COVID-19 antibodies in the county to be 4.1%, with a range that could be as low as 2.8% and as high as 5.6%, when you factor in the reliability of the tests.

An estimated 221,000 adults to 442,000 adults at the high end may have been infected at some point before April 9 with COVID-19, suggesting that the number of total people in the county with a past or current infection is 28 to 55 times higher than the number of reported positive cases, Dr. Barbara Ferrer, L.A. County’s public health director said Monday.

[…]

Although the sample size was relatively small, Ferrer shared some early estimates about who was most likely to be infected:

Men were more likely than women to be infected. The estimated prevalence is 6% among men and 2% among women

7% of African Americans, 6% of whites, 4.2% of Asians and 2.5% of people who were Latinx who were tested were found to be positive for COVID-19

2.4% of people who were between the ages of 18-34 were positive

5.6% were between 35 and 54

4.3% who were 55 and older tested positive

(4) And in what is rather distressing reading, Die Welt (in German) wonders why neighboring Belgium (!) has the highest pro capita COVID19 mortality in the world — actually, the absolute numbers are larger than Germany’s, which has seven times the population of Belgium! Summarizing a few of their points:

(a) Belgium counts deaths “with” COVID19 as COVID19 deaths, in the name of “transparency”, even if the cause of death is different. Germany uses a  more restrictive definition.

(b) 50-70% of all deaths in Belgium are in homes for the elderly [about 20% of care home residents over 85 test positive in facilities where everybody was tested]. Die Welt cites a report in Belgium’s largest French-language daily, LE SOIR  Wie die Tageszeitung „Le Soir“ berichtet]  Staff went around without even face masks for weeks because of (c)

(c) there is an acute shortage of PPE, particularly masks. The emergency stockpile (from SARS days) had been destroyed pre-epidemic as it had passed the expiration date — and had not been replenished even though that could then easily have been done. (Now Belgium was forced to startup domestic production. [Becoming dependent on China is a recipe for disaster across the world.])

(d) Nevertheless, it’s not all doom and gloom. Spread in the general population has been contained, the number of cases grows more slowly, and the number of deaths has peaked and is now holding at about 300/day. But this is cold comfort, or as you say in both Dutch and German, “meager comfort”…

(e) Finally, as things are again picking up at my day job, I am grateful to the people who have started sending me article tips! 

COVID19 update, April 20, 2020: sensitivity to sunshine and humidity strongly suggests seasonality

(1) So how seasonal is COVID19? A preliminary technical report from the Department of Homeland Security’s scientific and technical division offers clues. Yahoo News obtained a copy https://news.yahoo.com/sunlight-destroys-coronavirus-very-quickly-new-government-tests-find-but-experts-say-pandemic-could-still-last-through-summer-200745675.html

To cut a long story short: the researchers exposed virus samples to artificial sunlight of varying intensity. The half-life of the virus in the equivalent of midday sun at mid-US latitudes was two minutes: that meant in practice that just 20 minutes, or ten half-lives, would kill 99.9% (or to be precise, 1023/1024) of the viruses. In weaker sunlight, the 

For influenza viruses, a 2009 PNAS paper (http://doi.org/10.1073/pnas.0806852106; editorial commentary at http://doi.org/10.1073/pnas.0900933106 ) showed an inverse relationship between absolute humidity and virus survival/transmission. From the preliminary findings of the DHS group, it appears that the same applies to coronaviruses. Cold and dry weather is best for virus ‘survival’, hot and humid worst; dry but abundant sunshine will still whack it.

These findings suggest that the COVID19 epidemic likely will exhibit similar seasonality as influenza, and that it will be less virulent in sunny climates. I notice Australia and South Africa got off pretty light this round, as these countries were in their antipodal summer and early fall: I assume many are bracing there for an antipodal winter resurgence at the same time as the epidemic might die out in the north. Hopefully, by the time we might see a second winter-spring wave of COVID19 in the Northern hemisphere, there should be a vaccine available.

(2) was the virus already in California in November? Via Erik Wingren, here is a Twitter thread by viral geneticist Trevor Bedford (Fred Hutch and U. Of Washington) that appears to debunk this theory, based on analysis of patient samples from the Seattle Flu Study. 

https://threadreaderapp.com/thread/1249414291297464321.html

“We confirmed that these samples from acute respiratory infections from Oct 2019 through Feb 2020 contained a variety of different viruses including influenza, RSV, rhinovirus, metapneumovirus and seasonal coronavirus. […S]easonal coronaviruses are responsible for ~30% of common colds and are easily distinguished from #SARSCoV2 (the virus responsible for COVID-19) in molecular assays. There is no chance of confusion between these in our assay.[…] If we restrict to viruses sampled in California (highlighted here as larger yellow dots) we see that they fall in with the rest of the US epidemic. There is no chance SARS-CoV-2 was circulating in California in fall 2019. Circulation in CA started in Jan or Feb 2020.Estimating total number of infections is difficult without serology[…] but I’d guess that we’re catching between 1 in 10 to 1 in 20 infections as a confirmed case.  

This would give 5-10 million infections in the US or about 2-3% cumulative prevalence. This is a long way from the 50% (R0 of 2) to 66% (R0 of 3) we’d need for herd immunity. I see #TestTraceIsolate as the only real solution to the problem we’re facing, alongside non-economically disruptive distancing and broad use of masks.”

(3) The “positivity rate” as a metric. This article https://www.theatlantic.com/technology/archive/2020/04/us-coronavirus-outbreak-out-control-test-positivity-rate/610132/ argues in favor of using the percentage of tested people who test positive as a metric for the severity of an epidemic. Seems a little bass-ackwards at first, since normally this will be influenced by how many test kits are available (if they are scarce, normally only people strongly suspected of being infected will get tested), but he does note an intriguing correlation between the positivity rate and the severity of an epidemic.

COVID19 update, April 19, 2020: Israel reopens; NYC vs. rest of USA; quick takes

(1) Today, Israel started Phase 1 of its “back to normality” plan. There appears to have been intense tug-of-war between economic and healthcare decision makers, which resulted in some tradeoffs. Masks were made mandatory, giving in to a strong demand from the Health Ministry, but in compensation, a large number of retail stores that were only supposed to reopen in Phase 2 are doing so right now.

I treated myself to a long walk around the Tel Aviv borough where I live. About 2 in every 3 stores was open for business, and of the remainder, some were setting up for reopening.

(2) Matt Margolis enters into the differences between NYC and the rest of the USA as far as COVID19 is concerned.

The numbers are shocking. Downstate has been so heavily impacted by the coronavirus that it skews the United States when you compare us to the rest of the world.

Downstate New York technically includes New York City, Long Island, and the Hudson Valley, but I am only including Kings, Queens, New York, Suffolk, Bronx, Nassau, Westchester and Richmond Counties. These counties have a population of 12,205,796, according to World Population Review’s numbers for 2020—bigger than many countries.

It’s currently claimed that the USA “leads the world in COVID19 cases and deaths”. In fact, as Matt points out, in confirmed cases per capita, the US is only #7 worldwide (Spain is #1). Bad enough, you say? But if we treated greater NYC/”downstate New York” as a separate country, it would have #1 worldwide by a longshot — with four times the per capita incidence of Spain at #2. “USA minus NYC” would only be #14 worldwide. In per capita fatality rates, the whole USA comes at #8 [I suspect actually as #9, since Sweden appears to be omitted in that list], but NYC treated as a country would again be the #1 by far, with double the mortality of the #2 (Belgium). “USA minus NYC” drops to #11.

(3) Germany apparently is starting broader community testing for antibodies. On a related note (via Instapundit), physicians from Mass General Hospital tested 200 random people in the marketplace of Chelsea, MA, and found that 1/3 had antibodies for COVID.

(4) The Great Decoupling? Legal Insurrection reviews worldwide signs of countries “socially distancing” from the Chinese communist regime. Even Emmanuel Macron [!] now seems to get it.

(5) The German tabloid BILD reports on successful use of Remdesivir in Munich. With every new report, I’m getting more positive about that drug.

(6) Prof. Jonathan Gershoni of Tel-Aviv U. claims to be “2/3 of the way toward a vaccine”. The basic idea of most vaccine developers seems to be to target the “spikes” of the coronavirus, which are responsible for getting cells to let the virus in. If the virus were to lose those in a mutation-evolution process in an attempt to ‘get around the vaccine’, it would become a lot less dangerous anyhow.

(7) And it appears that some applied mathematicians who noticed a repeated empirical pattern in the progress of the epidemic in several countries may have rediscovered Farr’s Law.

COVID19 update, April 18, 2020: community testing in Silicon Valley reveals huge “stealth infection numbers” — or does it?

A group of researchers around Eran Bendavid of Stanford (John Ioannides was among the many co-authors) yesterday released the results of their community testing effort in Santa Clara County, CA, as a preprint on MedRXiv: http://doi.org/10.1101/2020.04.14.20062463

Santa Clara County (where I was on assignment for a couple of years) is basically Silicon Valley: Palo Alto (of Stanford University fame), Mountain View (where Google’s campus is located), Sunnyvale, Cupertino (basically Apple City at this point), San Jose, and the like. As the authors explain:

At the time of this study, Santa Clara County had the largest number of confirmed cases of any county in Northern California (1,094). The county also had several of the earliest known cases of COVID-19 in the state – including one of the first presumed cases of community-acquired disease – making it an especially appropriate location to test a population-level sample for the presence of active and past infections.

So they recruited 3,439 volunteers through location-targeted ads on Facebook, and administered antibody tests to them. After discarding unusable results (unable to draw blood, volunteer appeared from outside county,…) this left them with 3,330 data points. The novel kit (Premier Biotech, Minneapolis, MN) they were using is not yet FDA-approved, so they ran calibration tests themselves at a Stanford lab, using positive and negative control samples [1].
Then they reweighted the results by sex (the sample skewed female), ethnicity, and ZIP code distribution to more closely match the overall Santa Clara County population. They also corrected for the test kit’s performance.

The results look like a bombshell, suggesting a Dunkelziffer (dark [case] number, stealth [case] number) as high as 50:1 or even 85:1.

The unadjusted prevalence of antibodies to SARS-CoV-2 in Santa Clara County was 1.5% (exact binomial 95CI 1.11-1.97%), and the population-weighted prevalence was 2.81% (95CI 2.24-3.37%). Under the three scenarios for test performance characteristics, the population prevalence of COVID-19 in Santa Clara ranged from 2.49% (95CI 1.80-3.17%) to 4.16% (2.58-5.70%). These prevalence estimates represent a range between 48,000 and 81,000 people infected in Santa Clara County by early April, 50- 85-fold more than the number of confirmed cases.

However (hat tip: Alex Pournelle, son of the late lamented Jerry Pournelle) biotech entrepreneur Balaji Srinivasan (himself a Stanford Ph.D.) posted an elaborate peer review on Medium in which he criticizes the statistical and sampling methodology of the authors. Let me summarize his two main critiques: (1) He points out that even the small number of false positives found in the manufacturer’s test calibration (none were found in Stanford’s own recalibration, but that is quite possible given the small sample) might mean a significant chunk of the detected rate could be false positives.
(2) In addition, as COVID19 tests were very hard to come by in Santa Clara County (or anywhere else) at the time, respondents to the ad would be self-selected for people suspecting they had COVID19 at some point, being unable to get tested for love or money, and jumping at the opportunity to get tested for free (my paraphrase).

While (1) would make me look toward the low end of the 95% confidence interval of the authors, the effect of (2) is hard to quantify. The authors would presumably retort that the two whole-community testing efforts known — Robbio, Italy (10%) and Gangelt, Germany (14%) — obtained even higher infection rates.

Erik Wingren drew my attention to an even more peculiar finding: in Boston, the denizens of a homeless shelter were tested [2]. “Of the 397 people tested, 146 people tested positive. Not a single one had any symptoms. […] The 146 people who tested positive were immediately moved to two different temporary isolation facilities in Boston. According to O’Connell, only one of those patients needed hospital care, and many continue to show no symptoms.” On the one hand, you’d expect this population to be extra vulnerable — on the other hand, some might argue that anybody who can survive on the streets for an extended period of time, exposed to every possible and impossible community pathogen, likely would have built up a pretty solid immune response. On the gripping hand [3], this is a completely novel pathogen. Any coronaviruses they would have been exposed to thus far would be a subset of common colds. (Most common colds are actually caused by rhinoviruses, which are a different family.)

The results of Eran Bendavid et al. appear to imply that the actual infection fatality rate (IFR) of COVID19 is closer to the 0.1% of a nasty seasonal flu — which of course would have drastic public policy consequences. Taking into account the criticisms of the open peer reviewer would revise the IFR upwards — but still nowhere near the 5-10% CFRs (case fatality rates) thrown around for some countries with problematic testing availability.
I would say that this 0.1% represents a lower bound for the IFR, and the about 1.15% IFR found in Israel (which counts asymptomatic positive cases as patients) with a “young” population pyramid, and the about 3.1% CFR (case fatality rate) with a much “older” population pyramid found in Germany, can be taken as upper bounds. (I note that the preprint of Bendavid et al. makes no mention of age distribution adjustment explicitly says “We did not account for age imbalance in our sample” — which is significant considering morbidity and especially mortality go up strongly with age.)
Iceland continues to test more people, at this point reaching 11% of its entire population (by far the largest of any country). They found 1,754 confirmed infections out of 39,536 tested, or 4.4% — but with a truly self-selecting sample (anybody who wants to do so can get tested for free in Iceland — but this sample would obviously be skewed toward people who suspect they may have been exposed). They have seen only 9 deaths — corresponding to an infection fatality rate of 0.5% that I suspect is fairly close to the true IFR for a typical European age pyramid.

FOOTNOTES:
[1] “Among 37 samples of known PCR-positive COVID-19 patients with positive IgG or IgM detected on a locally-developed ELISA test, 25 were kit-positive. A sample of 30 pre-COVID samples from hip surgery patients were also tested, and all 30 were negative. The manufacturer’s test characteristics relied on samples from clinically confirmed COVID-19 patients as positive gold standard and pre-COVID sera for negative gold standard. Among 75 samples of clinically confirmed COVID-19 patients with positive IgG [antibodies], 75 were kit-positive, and among 85 samples with positive IgM [antibodies], 78 were kit- positive. Among 371 pre-COVID samples, 369 were negative.”

[2] A discussion of homelessness in the USA, and its relation to the deinstitutionalization movement, would be fodder for another (perhaps future) blog post.

[3] I couldn’t resist the Niven/Pournelle reference

UPDATE: John Campbell in his video today mentions both the Stanford study and the Boston homeless shelter, and points out a Dutch dataset I wasn’t aware of. They checked blood of 10,000 regular blood donors for antibodies. 3% of all samples had COVID19 antibodies. Since John cannot see how blood donors would somehow be more susceptible for infection than the general population, he assumes the 3% figure is representative of the infection rate in the Dutch population. With a population of 17.3m, that implies 519,000 Dutch have been infected (most of them apparently asymptomatic or with mild symptoms they misattributed to common colds or flus) — about 3% of the Dutch population, surprisingly similar to the Stanford study, and about 17x more than the official 30,619 cases diagnosed. This also implies the actual IFR in the Netherland is not 3,459/30,619=11.2%, but 1/17th that=0.66%. Hmm… not far from the 0.5% or so from the Iceland data…

COVID19 update, April 17, 2020: Breaking (good) news about remdesivir; ventilators questioned again. UPDATE: UV-C irradiation as an antisepsis technique

A number of clinical trials are going on with the nucleotide analog remdesivir.

Remdesivir, a.k.a. GS-5734

Now news is breaking on various news sites that one of the clinical trials, on 125 patients at U. of Chicago Medical Center, showed great promise. The orginal report appears to come from the medical statistics website STATNEWS. Some quotes:

The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir. 

“The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital. 

Her comments were made this week during a video discussion about the trial results with other University of Chicago faculty members. The discussion was recorded and STAT obtained a copy of the video.

[…]

Mullane, while encouraged by the University of Chicago data, made clear her own hesitancy about drawing too many conclusions.

“It’s always hard,” she said, because the severe trial doesn’t include a placebo group for comparison. “But certainly when we start [the] drug, we see fever curves falling,” she said. “Fever is now not a requirement for people to go on trial, we do see when patients do come in with high fevers, they do [reduce] quite quickly. We have seen people come off ventilators a day after starting therapy. So, in that realm, overall our patients have done very well.”

She added: “Most of our patients are severe and most of them are leaving at six days, so that tells us duration of therapy doesn’t have to be 10 days. We have very few that went out to 10 days, maybe three,” she said. 

There was anecdotal evidence from the start that remdesivir — originally developed for ebola, and previously shown to be active in vitro (i.e., in the test tube) against coronaviruses — was effective in at least some COVID19 patients. There were two early cures during the Washington state outbreak, and in Israel, “patient #16”, a tour bus driver who got severely ill after ferrying a group of infected pilgrims around for days, quickly recovered when given the drug as a last resort. Also, last week, a small trial was published in the prestigious New England Journal of Medicine.

Unlike the several mechanisms proposed for hydroxychloroquine, the mechanism by which remdesivir works is clearly understood and unambiguous. In plain English, the drug [*] pretends to be the letter A of the genetic alphabet, but when the enzyme RdRa (RNA-dependent RNA polymerase) starts making copies of the virus RNA and it grabs the “fake A” instead of a real A (adenosine), the next letter has nowhere to go, and copying breaks off. (This is not something I can see an easy way for the virus to quickly mutate-and-evolve its way into resistance for: making RdRa so clever it can tell the difference between real A and fake A? Developing an enzyme that selectively “eats” the fake A?)

The theory sounds good, and was confirmed in the test tube and in an “animal model” (in this case, rhesus monkeys): but many drug candidates that ticks all the boxes in the lab fall flat when administered to actual human patients. Fortunately, testing for safety and side effects in humans had already been completed years ago, when Gilead Sciences first tried to obtain FDA approval for its use in ebola. Thus, clinical trials could skip these steps and immediately proceed to actual clinical effectiveness tests.

I am looking forward to the final public release of data, but this looks quite promising.

Elsewhere on STATNEWS, I found another story reviewing the evidence (some of it covered here in earlier updates) about ventilators in a COVID19 setting, and how in many cases noninvasive respiration appears to be the preferred alternative. Read the whole thing.

In the US, President Trump has unveiled a staged “Opening Up America Again” plan (full text available at the link). The plan is attacked by some as being too timid and laying out unrealistic threshold conditions . Others say that it reflects a compromise between epidemiological and economic imperatives. We link, you decide.

Finally, Israeli PM Benjamin “Bibi” Netanyahu signed off in principle on a staged plan for reopening the Israeli economy, to be voted on in a cabinet meeting tomorrow night.

Unless important news breaks tomorrow, I will probably skip updates on the sabbath. Shabbat shalom, and to the Eastern Orthodox Christian readers, a meaningful Good Friday and a happy Easter. And to all: stay healthy and safe!

[*] technically, remdesivir is what pharmacologists call a prodrug, i.e., a molecule that within the body reacts to release the active drug component.

UPDATE: Dr. Seheult on remdesivir and on a novel approach to keeping hospital rooms and public spaces sterile: far UV-C lamps. UV-C light is the type of “hard” UV radiation that is blocked by the earth’s ozone layer. Far UV-C (207-222nm) is high enough energy to destroy bacteria and viruses, but too short-waved to penetrate further than the top layer of cells — therefore does not cause skin cancer or cataracts.

COVID19 update, April 16, 2020: Germany’s exit roadmap; brief Belgium update; UPDATE: Switzerland’s time table

A light edition today, as I’ve returned to work post-Passover.

Germany appears to have passed the peak of the infection, and for several days running now has seen recoveries exceed new infections.

Consequently, the number of active cases is dropping:

Austria is about a week further along on this trajectory, and started reopening yesterday. Now the German Chancellor, Angela Merkel, has announced a roadmap for Germany’s return to normality yesterday, Some key points translated from the German “breaking news” report (and from the original document, see below):

• Stores smaller than 800 m2 (about 8,800 sq.ft.) will be allowed to reopen Monday April 20, with hygiene and distancing measures. The motivation appears to have been to exclude indoor malls and stores that functionally operate as such from the initial opening permit.
• In addition, bike stores, automobile dealerships, and bookstores can reopen on the same day regardless of floor area.
• Also allowed to open on the same day are zoos, public parks, botanical gardens, and libraries.
• Schools will gradually reopen May 4, beginning not with the youngest (as Israel is considering), but with classes in their final exam years, as well as the final grade of elementary school.
• hairdressers and cosmeticists can reopen May 4 (with protection)
• mass public events such as concerts, festivals, soccer matches, etc. will remain banned until August 31.
• the Free State of Bavaria/Bayern will wait an additional week beyond these deadlines, as it was particularly hard-hit. In general, the Länder (lands, constituent states of the Federal Republic) will have leeway in working out details.
• industrial activity is to carry on as normally as possible, under observance of social distancing, and telecommuting where at all feasible. In sectors where standstills have occurred due to lacking supply of components or spare parts from abroad, the government is to step in to help secure these
• agriculture, it seems, was never restricted in any way (thank G-d)
• masks are strongly recommended for any situation where it is impossible to keep a distance of at least 1.5m (5ft), e.g., on public transit
• people are strongly urged to avoid all unnecessary travel within the country. Travelers abroad are still subject to a 2-week quarantine upon return, with exceptions for those transporting goods (e.g., truck drivers) and for cross-border commuters in border areas.
• hotels and travel services can resume limited activity for necessary travel, not for leisure tourism

Note that the original report in DIE WELT was (understandably, given the “hot” breaking news character) written in great haste, and contained a capital mistake concerning religious services, implying that they would remain prohibited indefinitely. Predictably, this led to considerable commotion both in Germany and abroad.

However, here is the full document from the Bundesregierung (Federal Government), which instead says:

The Federal Chancellor and the heads of government of the Länder [i.e., the semi-autonomous “lands”/member states/top-level provinces that made up the Federal Republic] are aware that the practice of religion is a particularly valuable asset and, especially against the background of the difficulties that this epidemic and its consequences are causing for many people, living faith gives strength and confidence. However, after all we know about the role of meetings in the spread of the virus and about the risk of infection and the serious consequences for vulnerable groups [read between the lines: attendance at places of worship is heavily skewed to older people], it is still urgently necessary to limit ourselves to the transmission of religious content through the media. Meetings in churches, mosques, synagogues as well as religious ceremonies and events and the meetings of other religious communities should not take place for the time being. The Federal Ministry of the Interior, Building and Homeland Affairs, together with representatives of the Prime Minister’s circle, will begin talks with the major religious communities this week in order to discuss a way forward that is as consensual as possible.

In other words: I expect places of worship to reopen, with distancing restrictions (in practice: a cap on attendance), sometime in May unless an agreement can be reached very quickly. Lest anybody doubt the role of religious ceremonies in spreading an infection like this: Israel had major “super-spreading” events during Purim celebrations and closed down all communal houses of prayer (synagogues included) for the duration. What’s more: two ultra-Orthodox communities where rabbis at first continued to operate synagogues and yeshivot (communal religious academies) in defiance of the order now account for about 40% of all COVID19 cases in Israel. The virus doesn’t care whether you’ve come to pray, to watch a soccer match, or to hear Dream Theater play their new album — from its perspective, they are all large crowds of people packed together.

The same full document also stresses what I call TTT (test, track, trace) as a cornerstone of the strategy. Present testing capacity is stated as 350,000 a week. (Germany avoided the mistake of the CDC and decentralized testing from the start, with individual Länder harnessing the private sector.)

Meanwhile in next-door Belgium, a similar “roadmap” is being worked on but has yet been published. Instead, existing restrictions are being trimmed ad hoc at the margins. For example, about a week ago cell phone and telecommunications stores were added to the “permitted essential businesses” list, and both garden supplies stores and DIY stores are now allowed to reopen.

UPDATE: Switzerland is reopening April 27 (except for Ticino/Tessin canton bordering on Italy, which got it bad and will follow later). The Neue Züricher Zeitung has details (in German): https://www.nzz.ch/…/corona-ausstiegsstrategie-der…

Briefly:
27 April: Garden centers, flower shops, DIY shops, etc…. also with hygienic measures: hairdressers, massage, beauty salons.
11 May: remaining stores
8 June: middle schools, vocational schools, high schools, zoos, museums.
TBD: restaurants (Swiss don’t eat out as much as Americans in urban areas tend to do, BTW), touristic infrastructure, recreational facilities like swimming pools.

COVID19, April 15, 2020 update: Cytokine storm — the immune system “killing the patient in order to save him/her”

The more I read about the (fairly rare) cases of younger people in generally good health dying or becoming critically ill, the more it sounded to me like “cytokine storm”, a.k.a. https://en.wikipedia.org/wiki/Cytokine_release_syndrome

In plain English, this is what happens when the immune system massively overreacts and does more damage to the patient than the original disease. It is generally assumed that the vast majority of deaths due to the 1918 “Spanish” Flu [*] resulted from cytokine storm, which explains the (for a flu) anomalous age distribution of mortality.

A reader (thanks a lot, Lissa!) forwarded me a story from the San Diego Union Tribune about a doctor in the prime of his life who got infected caring for the first major outbreak in Washington State.  https://archive.is/YBqAq

A 6-foot-3, 250-pound former football star who played for Northwestern in the 1996 Rose Bowl, he wasn’t fazed by much.

“To worry about myself, as a 44-year-old healthy man, didn’t even cross my mind,” he said in an interview Monday.

But on March 12, with his wedding day two months away, Padgett became the patient.

Soon after being admitted to his own hospital with a fever, cough and difficulty breathing, he was placed on a ventilator. Five days after that, his lungs and kidneys were failing, his heart was in trouble, and doctors figured he had a day or so to live.

He owes his survival to an elite team of doctors who tried an experimental treatment pioneered in China and used on the sickest of all COVID-19 patients.

Lessons from his dramatic recovery could help doctors worldwide treat other extremely ill COVID-19 patients.

“This is a movie-like save, it doesn’t happen in the real world often,” Padgett said. “I was just a fortunate recipient of people who said, ‘We are not done. We are going to go into an experimental realm to try and save your life.’”

Once his colleagues at EvergreenHealth realized they had run out of options, they called Swedish Medical Center, one of two Seattle hospitals that has a machine known as an ECMO, which replaces the functions of the heart and lungs.

But even after the hospital admitted him, doctors there had to figure out why he was so profoundly sick.

Based on the astronomical level of inflammation in his body and reports written by Chinese and Italian physicians who had treated the sickest COVID-19 patients, the doctors came to believe that it was not the disease itself killing him but his own immune system.

It had gone haywire and began to attack itself — a syndrome known as a “cytokine storm.”

The immune system normally uses proteins called cytokines as weapons in fighting a disease. For unknown reasons in some COVID-19 patients, the immune system first fails to respond quickly enough and then floods the body with cytokines, destroying blood vessels and filling the lungs with fluid.

The doctors tried a drug called Actemra [US brand name for the immunosuppressor https://en.wikipedia.org/wiki/Tocilizumab] which was designed to treat rheumatoid arthritis [an autoimmune disease] but also approved in 2017 to treat cytokine storms in cancer patients.

“Our role was to quiet the storm,” said Dr. Samuel Youssef, a cardiac surgeon. “Dr. Padgett was able to clear the virus” once his immune system was back in balance.

Dr. Matt Hartman, a cardiologist, said that after four days on the immunosuppressive drug, supplemented by high-dose vitamin C and other therapies, the level of oxygen in Padgett’s blood improved dramatically. On March 23, doctors were able to take him off life support.

Four days later, they removed his breathing tube. He slowly came out of his sedated coma, at first imagining that he was in the top floor of the Space Needle converted to a COVID ward.

There are a number of theories why chloroquine and hydroxychloroquine (HOcq) appear to have at least to some therapeutic benefit in COVID-19 patients: one that it is a zinc metallophore and zinc interferes with RdRa (RNA-dependent RNA polymerase, the enzyme that makes copies of the viral genome); another that it changes the intracellular pH to an extent that interferes with viral reproduction; yet another that it has some protective effect on hemoglobin. But the real answer may have been staring us in the face all the time:  HOcq, aside from being a decades-old antimalarial, also happens to be a mild immunosuppressant, and has been used as such (initially off-label) for many years (under the US brand name Plaquenil) in patients with autoimmune diseases like lupus and rheumatoid arthritis. So its real benefit may be in holding cytokine storm at bay, and stopping the immune system from “killing the patient in order to save him/her”. 

Now a downregulated immune system will result in greater vulnerability to opportunistic bacterial superinfections — which is why the simultaneous administration of an antibiotic like azithromycin (“Z-pak” as it’s popularly known in the US) appears to give added value to the treatment. As for the recommendation of adding zinc: I already commented on that yesterday.

As I am writing these lines, it occurred to me that cytokine storm and “killing the patient in order to save him/her” may be perfect metaphors for extended (6-months and more) economic shutdowns that are sure to kill or irreparably damage an economy. I am perhaps the last person on the planet to dispute the usefulness of lockdowns and social distancing measures where appropriate. My own country has applied them severely, but this makes complete sense given our population density. They should not be applied as blunt instruments in a one-size-fits-all approach, and (at least this is widely discussed here) cannot be kept up for more than a limited time.  To give an example: applying the same standards across a continent-sized country, whether it is thinly populated Wyoming or teeming New York City, makes no sense. New York City and its commuter counties in adjacent states New Jersey and Connecticut account for nearly half the new cases AND mortality in the US — it was pointed out to me by my friend David S. Bernstein that the hardest-hit counties proportionally are not Manhattan (as one might naively expect based on population density) but the commuter counties. I can hardly think of a riskier prospect in a major respiratory epidemic than having to commute half an hour or an hour each way packed like sardines in a subway. (As far as I can tell from the New York Municipal Transit Authority website, the subway is still running, albeit with reduced service.) The same people who would want to apply the “if it only saves one life” standard to justify asinine measures like prohibiting the sale of seeds and gardening tools in Michigan supermarkets should instead direct their energies to New York City — where public transportation is likely responsible for more infections than all the “nonessential purchases” in the rest of the country combined. (But then, of course, they would not be able to make political hay off it…) It makes complete sense to keep NYC under lockdown for a considerable while longer. It makes none at all to do the same for agriculture and food processing — which would add famine to the already staggering economic cost of the pandemic.

POSTSCRIPT: Meanwhile, the Washington Post, in a rare display of journalism, dropped a bombshell (archive copy at http://archive.is/Tg5oo in case it gets “airbrushed”)” It appears that my friend “masgramondou” was not far off the mark with his origin theory for the epidemic.

In January 2018, the U.S. Embassy in Beijing took the unusual step of repeatedly sending U.S. science diplomats to the Wuhan Institute of Virology (WIV), which had in 2015 become China’s first laboratory to achieve the highest level of international bioresearch safety (known as BSL-4). WIV issued a news release in English about the last of these visits, which occurred on March 27, 2018. The U.S. delegation was led by Jamison Fouss, the consul general in Wuhan, and Rick Switzer, the embassy’s counselor of environment, science, technology and health. Last week, WIV erased that statement from its website, though it remains archived on the Internet.

What the U.S. officials learned during their visits concerned them so much that they dispatched two diplomatic cables categorized as Sensitive But Unclassified back to Washington. The cables warned about safety and management weaknesses at the WIV lab and proposed more attention and help. The first cable, which I obtained, also warns that the lab’s work on bat coronaviruses and their potential human transmission represented a risk of a new SARS-like pandemic.

“During interactions with scientists at the WIV laboratory, they noted the new lab has a serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory,” states the Jan. 19, 2018, cable, which was drafted by two officials from the embassy’s environment, science and health sections who met with the WIV scientists. (The State Department declined to comment on this and other details of the story.)

The Chinese researchers at WIV were receiving assistance from the Galveston National Laboratory at the University of Texas Medical Branch and other U.S. organizations, but the Chinese requested additional help. The cables argued that the United States should give the Wuhan lab further support, mainly because its research on bat coronaviruses was important but also dangerous.

As the cable noted, the U.S. visitors met with Shi Zhengli, the head of the research project, who had been publishing studies related to bat coronaviruses for many years. In November 2017, just before the U.S. officials’ visit, Shi’s team had published research showing that horseshoe bats they had collected from a cave in Yunnan province were very likely from the same bat population that spawned the SARS coronavirus in 2003.

“Most importantly,” the cable states, “the researchers also showed that various SARS-like coronaviruses can interact with ACE2, the human receptor identified for SARS-coronavirus. This finding strongly suggests that SARS-like coronaviruses from bats can be transmitted to humans to cause SARS-like diseases. From a public health perspective, this makes the continued surveillance of SARS-like coronaviruses in bats and study of the animal-human interface critical to future emerging coronavirus outbreak prediction and prevention.”

The research was designed to prevent the next SARS-like pandemic by anticipating how it might emerge. But even in 2015, other scientists questioned whether Shi’s team was taking unnecessary risks. In October 2014, the U.S. government had imposed a moratorium on funding of any research that makes a virus more deadly or contagious, known as “gain-of-function” experiments.

[…]

There are similar concerns about the nearby Wuhan Center for Disease Control and Prevention lab, which operates at biosecurity level 2, a level significantly less secure than the level-4 standard claimed by the Wuhan Insititute of Virology lab, Xiao said. That’s important because the Chinese government still refuses to answer basic questions about the origin of the novel coronavirus while suppressing any attempts to examine whether either lab was involved.

[*] The reason for the historical name “Spanish Flu” is simple. There were outbreaks in army barracks across the front, but those were hushed up due to wartime censorship. Spain was neutral in WW I, so its press was the first to significantly report on the epidemic. The name “Spanish” has stuck until quite recently.

ADDENDUM: welcome Instapundit readers! Via your intrepid host linking a NYPost article, I found this recent study from MIT showing the major role the NYC subway had in spreading the infection. This is my face. It is shocked.

ADDENDUM 2: I linked an interview with South Korean COVID19 expert Dr. Woo-Joo Kim of Korea University Guro Hospital in an earlier update. Commenter “reactionary” on Instapundit drew my attention to the followup interview, which is highly recommended (remember, South Korea was one of the first countries to get the epidemic under control). He starts discussing cytokines and cytokine storm about 14 minutes into the video (in Korean with English subtitles).

COVID19 update, April 14, 2020: vitamin D, zinc, testing; end of globalization as we know it?

(1) Roger Seheult MD in his latest update gives a clear discussion of RT-PCR (reverse transcriptase polymerase chain reaction) testing vs. antibody testing.

I spoke to an industry insider about why not more antibody testing yet? I was told that first-generation antibody testing kits achieved accuracies of around 30%, which are “worse than useless”. But accuracies are steadily improving, and we should soon be looking at something comparable in accuracy to a good RT-PCR.

In response to reader demand, Dr. Seheult also gives a link to a hydrotherapy regime that might be useful for prophylaxis and for treatment of mild cases — but only in addition to more conventional approaches: https://www.hydro4covid.com

(2) Nursing school instructor John Campbell, in his latest update, hammers a lot on the beneficial effect of vitamin D for the human immune system. In fact, he looks at the different mortality statistics for ethnic groups in NYC, and finds it fascinating that everybody comes up with socio-economic explanations while overlooking something obvious: at northern latitudes, vitamin D deficiency is quite common among dark-skinned people. (In fact, both the white and “yellow” skin types evolutionarily started as mutations that just happened to allow humans to thrive in less-sunny northern regions.)

He strongly recommends everybody who does not already enjoy abundant sunshine take vitamin D supplements to boost their immune systems — especially people with darker skin types.

On a related note, he looks at the surprisingly mild statistics of the epidemic in Australia, and notes that this militates in favor of seasonality — but again stresses the beneficial effect of vitamin D in the sunny Australian summer and early fall. (I note that South Africa too has so far dodged a major bullet.)

He also notes that homes for the elderly everywhere have appalling statistics — it takes only one or two cases to cause a major outbreak in one unless you really know what you are doing.

One more thing: out of 459 newly diagnosed cases in South Korea, 228 are imports from the USA. While he admits this will not be a representative sample of the US population (whoever still travels may be a businessman or some sort of expert), it does have implications for the Dunkelziffer/”dark case load” in the USA.

(3) Speaking of nutrition, a number of doctors advocate zinc supplements. [Full disclosure: I have been taking such since the beginning of the crisis.] This is emphatically not quack science: zinc is an essential nutrient, and in fact the most common transition metal in the body outside the bloodstream. (Iron in hemoglobin is the most common one if you include it.) Hundreds of physiological processes depend on zinc in the catalytic site of an enzyme, as a co-catalyst or modulator, or as a structural element. This includes the immune system too: I was struck between the similarity between some early COVID19 symptoms (such as loss of taste and smell) and those of zinc deficiency (presumably because Zn is mobilized in great amounts for the immune system). Here is an academic review article on the roles of zinc in the antiviral immune system.

Particularly people who live on vegetarian diets are at risk for Zn deficiency — those who primarily live on red meats or seafood least so.

(4) Urban geographer Joel Kotkin, in a must-read essay , explains how COVID19 (and whatever similar epidemics may lay in our future) will make dense urban centers less attractive to live in. He notes NYC accounts for nearly half of COVID19 mortality in the USA, greater Milan for half the cases in Italy and almost 3/5 of deaths,… “Simply put, pandemics are bad for dense urban areas, particularly those that are diverse and relatively free. This has been very much the case since antiquity. The more global and vital an urban system—Rome, Alexandria, Cairo, Venice, Florence, London, Paris—the more susceptible it is to the pandemics that seem to be occurring regularly over the past two decades. Cities no doubt will recover, particularly if real estate prices continue to fall, but the pandemics limit their upward trajectory and will continue to drive people elsewhere.”

On a related note, former director of the World Bank’s research department Branko Milanovic, https://www.standaard.be/cnt/dmf20200327_04904960 interviewed in De Standaard (in Dutch) argues that (my paraphrase) “We went for the extremes of globalization because technology enabled it. COVID19 showed such an economy is brittle.” He does see a return to some form of globalized economy the day after the crisis, but not again to this extreme extent.

It is noteworthy that such “the end of globalization as we know it” rhetoric is not the province of just the American populist “right”, but that one can hear similar voices around the globe and the political spectrum from the German establishment center-right to the left. I was (pleasantly) surprised to read a scathing article in The Guardian (!!) about the way some Chinese academic publications about the origins of the virus had to be airbrushed by CCP regime fiat. “Oceania is not at war with Eurasia.” [On a related note, Taiwan released an Email from December in which it warned the WHO about patients with a new, SARS-like lung disease.]

The American Interest looks at the long, hard road to decoupling from China. An article in De Standaard (in Dutch) entitled “[shoddy m]asks as a canary in the coalmine”, looks at the trend towards what it calls with an English neologism “reshoring” — bringing production back home to have better control over supply chain and especially quality. This process is said to have been going on for a while in Belgium, but is now being accelerated by COVID19.

Finally, feelgood story of the day: at age 107, a Dutch woman named Cornelia Ras is now the oldest person to survive a bout with COVID19 .

COVID19 update, April 13, 2020: Italy and Israel grappling with exit strategies

(1) Italy, which has seen mortality well past the peak and on a downward trend (on a moving average) since the beginning of the month, and where new cases are lowest since March 13, is starting to grapple with “the day after”. As reported earlier, both Austria and Denmark are starting the road back to normal on April 15, with Norway to follow suit on April 20. Spain has started some normalization measures today.

(2) Israel too seeks to emerge from its “induced economic coma”. [Not all sectors have been idled: in fact, transportation infrastructure works have been carried out ahead of schedule as they were minimally disruptive now.] COVID19 cases have crossed the five-digit threshold here and are still increasing, but this is nearly compensated by an upswing in the number of recoveries, leading to an apparent stabilization in the number of active cases. Sure, we’re not out of the woods yet, as deaths have now grown into triple digits, but according to deputy director general of the health ministry, Itamar Grotto:

“I think we can say that we’ve pretty much succeeded in the stage of stopping the spread” of the coronavirus. Speaking to Ynet, he said that although there could be unexpected results from the outbreak in Bnei Brak and some other [c]hare[i]di communities, which would only be seen in the next few days, “It can be said that we’re in a relatively stable situation, and we’re in the stopping phase. Now, we need to see how we get out of this.” 

A group of captains of industry and business published an open letter, calling to start reopening things after Passover, “or face economic collapse”. Well, according to Haaretz (h/t Mrs. Arbel; I will deviate from my usual policy of not sending links there) these are the recommendations of the National Security Council, in four phases:

Phase 1: could begin as early as Thursday. In a nutshell: 

• hi-tech and finance sectors reopen, as distance compliance etc. easier to assure there.
• Government offices, currently down to essential staff, are ramped up to 50% staffing again
• Preschools and special education are reopened. (Preschoolers are least in danger from the virus.)
• It is being considered to permit preparation of small groups of HS seniors for their Bagrut (matriculation) exams
• Public transportation, currently running on a severely curtailed schedule, to be partially restored again

Phase 2: two weeks later

• Reopen retail stores other than large shopping centers
• Elementary schools reopen

Phase 3: two more weeks later

• Reopen remaining stores
• Reopening cafes, restaurants, and hotels with social distancing and hygiene restrictions 
• Junior high and high schools reopen. Strict hygiene and social distancing required
• Universities and other postsecondary education will continue online teaching until the end of the school year, as they have already adapted to this
• large, crowded events will still be prohibited

Phase 4: only when pandemic is under full control

• Leisure and entertainment industries back in operation
• Flights resume
• Anyone over 60 and at-risk populations still under lockdown

One main worry expressed is whether, if a flare-up occurs, the public will abide temporary back-tracking.

Some might wonder if gregarious and notoriously “in your space, in your face” Israelis will adjust to a new normal of keeping at two arms’ length and no touching, hugging, backslapping, kissing,…

UPDATE: welcome, Instapundit readers!

COVID19 update, April 12, 2020: Easter edition

Happy Easter to my Christian readers. Below are a few COVID19 updates.

(1) Dr. Seheult from MedCram, who is actually a pulmonologist himself, weighs in on the “to ventilator or not to ventilator” debate in Episode 53 of his COVID19 video series. He references a paper by an Italian team that distinguishes two “phenotypes” of clinical presentations in severe COVID19 patients: about 20-30% are “type H” who fit the classic criteria of ARDS and can benefit from intubation, while the remainder are “type L” who are best managed with noninvasive techniques.

Dr. Seheult also cites a “white paper” on COVID19 case management by a colleague. Most interesting for some of us, perhaps, are the prophylaxis recommendations:

• Vitamin C 500 mg BID [=twice a day] and Quercetin 250-500 mg BID
• Zinc 75-100 mg/day (acetate, gluconate or picolinate). Zinc lozenges are preferred. After 1-2months, reduce the dose to 30-50 mg/day. [Full disclosure: I started doing this two weeks ago. Especially people on vegetarian diets, who often have zinc insufficiencies, should take supplements. Zinc plays an essential role in hundreds of processes in the body, including the immune system. If you exclude iron in hemoglobin, zinc is actually the most common transition metal in the human body.]
• Melatonin (slow release): Begin with 0.3mg and increase as tolerated to 1-2 mg at night [this appears to be primarily to ensure adequate sleep, which affects immunity]
• Vitamin D3 1000-4000 u/day (optimal dose unknown). Likely that those with baseline low 25-OH vitamin D levels and those living [north of the 40th Parallel] will benefit the most.

(2) An article in the Israeli business paper GLOBES looks at the “underworld” of medical equipment procurement. (H/t: Mrs. Arbel)

(3) Immunosuppressant drugs in COVID19? Erik Wingren brings this case in Washington State to my attention: https://komonews.com/news/coronavirus/experimental-drug-helped-critically-ill-emergency-room-doctor-recover-from-covid-19 The drug administered here is https://en.wikipedia.org/wiki/Tocilizumab, which was actually FDA-approved in 2017for the management of cytokine release syndrome, (“cytokine storm”) as a side effect of CAR-T cell immunotherapies. It is increasingly becoming clear that, while most younger patients weather the disease well if they are symptomatic at all, a small subgroup appears to be predisposed to cytokine storm — in plain English, a massive overreaction of the immune system that does more harm to the body than the disease itself. In such situations (only!), immunossuppressants may actually save lives. (Cytokine storm appears to have accounted for the majority of deaths in the 1918 “Spanish Flu” pandemic — which explains why young and otherwise healthy patients were often more at risk than ) For more on cytokine storm in influenza more broadly, see this paper and that paper.

(4) A fairly large-scale (440 patients) clinical trial is in progress at the Erasmus Hospital in Rotterdam, the Netherlands with plasma antibodies from healed patients. (This is technically known as “passive vaccination”.)

(5) No, it’s not just Trump: in an op-ed in the German center-right daily DIE WELT, entitled “Diese WHO gefährdet ons” (This WHO endangers us) a human rights activist blasts the WHO, its leadership, and its execrable behavior in the early part of the crisis. As she puts it, the current WHO chair knows he owes his job to Chinese support and has been a devoted piper playing the tune called by his meal ticket.

But what’s more, DIE WELT reports in its lead article that the German domestic intelligence & counterespionage service, the Verfassungsschütz (Constitution Protection ) registers intensive influence and recruitment operations of German civil servants and elected officials by the Chinese regime. The goal is to get them to parrot the Chinese propaganda line that the country is a leader in combating the outbreak and helping the whole world do so, and that the virus did not come from China. “Together, let’s write a fairy tale,” (Wir schreiben gemeinsam ein Märchen) Die Welt comments sarcastically

UPDATE 1: Denmark is reopening in stages starting Wednesday April 15. In the first step, kindergartens and primary schools will be reopened, as their charges are least at risk from the consequences of an infection. The country has seen hospital occupancy drop since the beginning of the month.

In Austria some shops reopen this Tuesday, followed by other stores, restaurants and hotels in May.
Children go back to Norway’s kindergartens on 20 April and junior schools a week later.
In Bulgaria farmers’ markets are reopening. In the Czech Republic, shops selling building materials and bikes are back in business and rules have been relaxed for open-air recreation areas.
Spain, which along with Italy has been hardest hit by Covid-19, aims to allow non-essential workers back to work from Monday and will hand out protective masks at stations.

COVID19 update, April 11, 2020: (1) how much of the COVID19 iceberg is below the waterline? (2) Miscellaneous updates

Lots ado now about “how much of the iceberg is below water”. In Germany and Austria they call this the “Dunkelziffer” (literally: “dark number”), i.e. how many people got infected and never diagnosed because either they never got sick, or had a mild form which they shrugged off as a garden-variety winter cold. You can already see the policy implications:  not only would this drastically reduce the assumed IFR (infection fatality rate), but it might imply that a nontrivial segment of the community might already have acquired antibodies for the virus. Not enough for true herd immunity, mind you, but even percentages as low as 15% would put a crimp on the reproductive number of the infection.

Several initiatives have been going on around the world to resolve this question. I already discussed Iceland in a previous blog post. Everybody there can get tested, and about 8.5% of the population (by far the largest percentage of any nation) has. This self-selected sample turned out to have about 50% of positives asymptomatic. (This squares with anecdotal evidence here in Israel.)

A community testing initiative is currently proceeding in Silicon Valley, led by Prof. Eran Bendavid of Stanford. 

https://www.sacbee.com/news/coronavirus/article241855856.html This was in part prompted by the intriguing observation that California’s death toll of 541 (as of April 9) is an order of magnitude lower than that of NYC alone! Plausible alternative explanations can be advanced — the highly congested character of NYC and widespread reliance on crowded public transit — David S. Bernstein pointed out to me that the hardest-hit counties per capital of NY state are not Manhattan (as one might naively expect), but “commuter counties” like Nassau and Long Island. 

Meanwhile, Germany and Austria have some first results about  the “Dunkelziffer”. AUSTRIA has released intermediate results from a random sample test of (thus far) 1,544 people: the study is now expanding its sample.  The official infection rate is 0.1%; the study finds 3 times that, but upon closer reading, the 95% confidence interval stretches from 0.12 to 0.76%. This absurdly large uncertainty band should narrow as the sample size increases: all else being equal, the width of the interval will be inversely proportional to the square root of the sample size. So to narrow the uncertainty by a factor of ten, they should test about a hundred times as many people.

In Germany, a virologist named Hendrik Streeck, head of the virology institute at Bonn University, took a different tack: he played “test everybody, sample everything” in the nearby small town of Gangelt (pop. 12,446 ) in the Heinsberg district (on the Dutch border). Heinsberg saw a massive outbreak about two weeks ahead of the rest of the German Federal Republic — it is broadly assumed that ‘super-spreader’ events took place at Carnival celebrations in Gangelt. [The somewhat sleepy Belgian town of Alken, best known for its Cristal brewery, became Ground Zero in that country in the same way.]

Testing is both for the viral RNA and for antibodies. A few takeaways from the study (German writeup in the Handelsblatt; another German writeup in Die Zeit; English writeup in Reason magazine )

• 80% of the population of Gangelt was tested
• 15% of the population has been infected at one point. [In contrast, Germany officially has 122,171 cases, out of a population of 83,783,942 — fewer than 0.15%. However, the infection rate in Germany is very heterogenous.
• 14% of the population has antibodies for the disease
• IFR (infection fatality rate) for the community is then calculated as 0.37%, compared to 2.24% from the national statistics. I infer that testing nationwide has been under-sampling by a factor of 5.5, and that thus there are about 4-5 “cases below the waterline” for every known case — people who never got sick at all, or had mild symptoms they misattributed to a common cold or a seasonal flu
• Streeck believes that even these 15% may be contributing to herd immunity
• While he has found traces of viral RNA on doorknobs, TV remotes, etc. in the houses of infected people (in one case even in the toilet water), there was no indication of viable virus particles that could cause an infection. He sees close and prolonged contact with carriers as the primary way of virus spreading, via droplets getting breathed or coughed upon others

This study has come under fire from German colleagues for methodological reasons, but the state government of North Rhine-Westfalia, which bankrolled the study, stands by Streeck

Elsewhere:

(1) a must-read article by Matt Ridley, a veteran popular science writer with a Ph.D. in biology, who also happens to be a member of the British House of Lords (as the 5th Viscount Ridley): “The bats behind the pandemic”. (The Wall Street Journal version is paywalled, but a free version is available on his blog.) Some of the content is also discussed in a highly entertaining 1h video interview with Ridley, where he also tells it like it is about the Pekinese Lapdog Society, er, the WHO.

(2) The Daily Telegraph looks at the search for a vaccine: https://www.telegraph.co.uk/global-health/climate-and-people/race-covid-19-vaccine-much-politics-science/ Their main source appears to be this article in Nature Reviews Drug Discovery: https://www.nature.com/articles/d41573-020-00073-5
according to which there are no fewer than 120 candidates are in development, 78 of them projects known to be active, six of those in Phase I clinical trials.

(3) A research group at the University of Hohenheim, Germany has put online a simple simulator for different containment measures. As always, a model is not reality: your mileage may vary. But this ‘toy model’ can be informative to experiment with nevertheless.

(4) Now not just in the US, but also in the UK, some ICU doctors are reconsidering invasive ventilation — does it actually do more harm than good? — and shifting focus to noninvasive techniques (oxygen cannulas, O2 concentrators, O2 masks).  Current treatment protocols are based on experience with ARDS (acute respiratory distress syndrome) by other causes — and there are indications COVID-19 is a different ball game.

I talked to a veteran medical professional in my own family (many thanks, “Yehuda”) and got a nuanced answer: paraphrasing, “it may be that the people put on invasive ventilation were basket cases to begin with and therefore would have had a high mortality in any case, but intubation is a tricky business requiring sedation and curarization to even enable the intubation — and with any tricky procedure, the success rate often depends on the skill of the person doing it.” This implies then that the limiting factor isn’t so much the availability of “ventilators” as the availability of personnel skilled in intubation. Noninvasive ventilation is of course way easier to do.

UPDATE: the first clinical trial results, in a population of severe and critical cases, of remdesivir (originally developed by Gilead Sciences for ebola) were published in the New England Journal of Medicine https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal mem- brane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

A list of additional remdesivir clinical trials in progress can be viewed here.