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:

(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, 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 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. 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


(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: Their main source appears to be this article in Nature Reviews Drug Discovery:
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

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.

COVID19 update, April 4, 2020: a brief look at Israel

The first case on Israeli soil was a returnee from the Diamond Princess cruise ship, who however stayed in isolation. A tourist returning from Italy appears to have been “Patient Zero”.

Israel was quick to stop flights with China. On 21 February, all returnees from South Korea or Japan were requested to go in 14-day home quarantine; subsequently the country placed a blanket 14-day home quarantine on all returnees rather than single out specific countries. At one point, 200,000 Israelis were in home quarantine — this number has dropped precipitously as most of the travel-related quarantines expired and were only partly compensated by new quarantinees who lived or worked with somebody who tested positive.

Unlike most countries, Israel counts everyone who tests positive as a patient, including asymptomatic cases. The only way to get off the list is to test negative.

As of the time of writing, 7,851 Israelis have tested positive, and the disease has claimed 44 lives so far (an apparent IFR of 0.6%). 126 patients are in serious condition, of which 108 on ventilators.

Most of the mild and asymptomatic cases are in home isolation, but several hotels have been commandeered by the government as an isolation option for asymptomatic and mild patients. About 700 patients avail themselves of this option at the time of writing. Once checked in, one can only leave after testing negative. Once checked in, one can only leave after testing negative for active virus.

The age profile of patients (like the population pyramid generally) is definitely younger than in the hardest-hit European countries, which is one factor that accounts for the low IFR.

Israel started introducing social distancing measures mid-March, but only started actively enforcing them later, then tightened them to the point of placing roadblocks. Everybody is confined to a 100m radius from home, except for shopping for essentials or medicines, to work at an essential job, or such. As of Thursday masks were made mandatory outside the home.

The effect of these measures can be seen in the COVID19 statistics about 10 days downstream: note the “kink” in the graph below that marks transition from doubling every 3 days, to doubling every 5 days or more.

Bnei Brak, a predominantly chareidi (fervently Orthodox) borough of Tel-Aviv, accounts for nearly 15% of all cases nationwide. This community regards considers communal religious study and activities to be its very reason for existence, and has hence been slow to embrace social raison d’être, especially as it eschews secular media sources. Recently the area has been placed on full lockdown.

Meanwhile elsewhere, even the WaPo is now assuming that the official fatality figures out of China are <understatement>severe underestimates</understatement>.

COVID19 update: March 23, 2020. What's in a name?

A reader asked me whether the scientific name is coronavirus, COVID-19, or something else. Without getting into the dispute over the common names, let me address that question specifically.

In a nutshell, coronaviruses are one major family of viruses. What they all have in common is their structure: They consist of a single strand of RNA which encodes the genetic “payload” , a shell of envelope proteins self-assembling around the strand, and a bunch of spikes on the shell whose job it is to stimulate receptors in the cell wall and effect an opening for entry. The spikes look like a kind-of ‘crown of thorns’ under an electron microscope, hence the name ‘coronavirus’.

The most common subgroup humans get exposed to are one type of common cold viruses (although most common colds are caused by rhinoviruses, a different family). There are other coronaviruses that are endemic in poultry and cause upper respiratory tract infections there. Others are endemic in bats, etc.

Alas, some coronaviruses are quite deadly to humans: SARS-nCoV (severe acute respiratory syndrome, novel coronavirus), also known as SARS-CoV, is the one that causes the disease simply named SARS. Originating in horseshoe bats, it somehow crossed the species border and caused a nasty epidemic in mainland China and Hong Kong, with another outbreak hitting Toronto hospitals. CFR (case fatality rate) of the disease is very high, at 9.6%, but no overt cases have reportedly been seen since 2004.

Another is MERS-CoV, causes MERS (Middle East Respiratory Syndrome, one colloquial name being “camel flu”). It apparently crossed the species barrier from bats to camels and thence (possibly via camel-based food products) to humans. MERS has a very high CFR (case fatality rate) of about 1/3 of diagnosed cases, but has a very low reproductive number (in part because it is so deadly?): since it was first described in 2013, we’ve had only about 2000 cases ever worldwide. An outbreak in South Korea in 2015 when a businessman returned from the Arab peninsula appears to have been when the South Koreans got their ‘dress rehearsal’ for how to deal with the present emergency.

The present virus is known as SARS-nCoV-2 because its RNA sequence is so similar (82 % sequence identity) to SARS-nCoV. The mutations that make up the difference (single-strand RNA viruses mutate very rapidly — for reason I’ll explain elsewhere) appear to have had two primary effects: (1) the virus is less deadly; (2) the spikes are more efficient at stimulating ACE2 receptors (angiotensin-converting enzyme 2), which it exploits to enter cells. (Remember, a virus that cannot enter a cell and take over its replication machinery can’t do much of anything. Like a computer virus without a computer ;))

What happens once the virus is inside, by the way? The RNA goes to a ribosome, which are the cell organelles that acts as  protein ‘assembly plant’ of our cells. Gene expression in our cells involves chunks of DNA getting copied onto “messenger RNA”, which then makes its way to the ribosome and gets translated into a protein (by assembling amino acids according to what the “tape” says, until it hits what biologists call a “stop codon”: an “end of message” marker, so to speak). When the viral RNA enters the ribosome instead, that merrily carries out the work order written on the “imposter”, such as the enzyme needed to clone the viral RNA (RdRA, or RNA-dependent RNA polymerase), the envelope proteins, and the spike proteins. There is considerable speculation that the spike proteins in SARS-nCoV-2 are more effective than those in SARS-nCoV.

COVID-19 (coronavirus disease, [first outbreak in] 2019) is what WHO settled on as the name for the disease, not the agent.

UPDATE: statistician and software developer Charlie Martin weighs in more on the Italy data.
And a Japanese financial website reports that the campaign to get the residents of Wuhan to “thank” their dictator backfired badly.
Also, some signs that maybe the anomalously good statistics from Japan may be the product of selection bias: see here (especially the comments) and here. One of the articles, however, made a collateral point I’ve brought up here before:

Cases of seasonal flu have been declining for seven straight weeks, just as the coronavirus was spreading, indicating Japanese may have taken to heart the need to adopt some basic steps to stem infectious diseases. Tokyo Metropolitan Infectious Disease Surveillance Center data shows that influenza cases this year are well below normal levels, with nationwide cases hitting a low according to data going back to 2004.

Also, after Sen. Rand Paul (R-KY), German Chancellor Angela Merkel is the latest politician to go into 14-day quarantine after the doctor or nurse who gave her a standard flu vaccine tested positive for COVID-19.

UPDATE 2: leaked documents appear to indicate that the claim that “there are no new cases in Wuhan” needs to be taken with LOTS of sodium chloride.

UPDATE 3: on the other hand, there is some good news hidden in all the bad (via Instapundit):
And this one gets the Möbius Dick Award: NYT claims travel restrictions didn’t work in China — for the period they weren’t implemented