COVID19 update, March 21, 2020: Dr. Matt Shelton on vitamin D; Harvard historian Niall Ferguson on how the pandemic exposed the “dysfunctional administrative state”; 2005 CDC paper touting chloroquine for SARS

(1) Dr. Matt Shelton, interviewed by Dr. John Campbell, tells us much more about vitamin D. Amusing statement: “Stay in the sun until you’re halfway to sunburned for your skin type, and you’ve had enough.”

(2) Niall Ferguson, about 10 minutes into this video from the Hoover Institute:

“The pandemic has revealed a terrible pathology at the heart of American political life, and it’s not the one you think. While the media endlessly pore over every utterance of President Trump, the real pathology that the pandemic has exposed is that we have a completely dysfunctional administrative state that is extremely good at generating PowerPoints and multiple-page reports, but when it comes to actually dealing with an emergency, is completely useless.”

Here’s another good one:

(3) My Facebook friend Jeff D. reminds me of a 2005 paper published by a group from CDC in the Virology Journal entitled: “Chloroquine is a potent inhibitor of SARS coronavirus infection and spread”.
http://doi.org/10.1186/1743-422X-2-69

And yes, that’s the old SARS-CoV-1, not the current SARS-nCoV-2 — but some of the people now doing all they can to “prove” HOcq doesn’t work would be quite embarrassed at this article.

(4) Meanwhile, Standard & Poor maintains Israel’s AA- sovereign credit rating, and predicts a “V-shaped recovery“.

Finally, another good one from Unherd: Prof. Karol Sikora, former head of The Who cancer program and Dean of the U. of Buckingham medical school, sounds a largely optimistic note.

 

COVID19 update: a brief look at three possible drugs; Bonus: a brief look at pre-existing conditions in Italy

Yesterday, the Israeli Ministry of Health fast-tracked approval for no fewer than eight experimental therapies for use.

Normally, Phase I, II, and III clinical trials on a drug take a lot of time and effort. But if you are merely repurposing an existing drug for another disease, you can short-circuit a lot of that since you already know safe dosage range and side effects.

These are the three that jumped out at me.

(1) Remdesivir was originally developed by Gilead Science as an anti-ebola drug. It worked against that virus in vitro (i.e. in the lab “test tube”) but not in vivo (i.e. in actual patients). It also worked in vitro against MERS and against the original SARS, so trying it against COVID-19 was worth at least a try.

Which is what was tried as a desperation roll of the dice on an early patient patient in Washington state, with apparently impressive success . Since then, increasing confirmation has been seeping in. Controlled clinical trials are in progress, with results expected next month.

Remdesivir is a so-called “nucleotide analog”. In plain English, it pretends to be a nucleic acid (i.e., a letter in the genetic code), but when the “imposter” is being incorporated in a piece of RNA instead of the real nucleotide, it has no place to attach the next one, and copying stops. Thus, the virus cannot reproduce.

(2) Favipiravir (sold in Japan under the brand name AVIGAN by Toyama Chemicals, a subsidiary of FUJIfilm). This was developed as a broad-spectrum anti-RNA-viral drug. It is an RdRA (RNA-dependent RNA polymerase) inhibitor, i.e., it interferes with the enzyme responsible for copying the viral RNA.

Japanese doctors apparently are using the drug, and China is running clinical trials.

(3) Chloroquine (a 70-year old generic antimalarial), and its close relative hydroxychloroquine, are at first sight the odd duck among the three. It’s obvious why the two above drugs could work, and it appears that they do. But why do we hear a lot about chloroquine these days? Last time I checked, malaria was not even a viral disease?

There is a fairly lucid explanation here of what is going on:

Zn2+ and RdRA discussion about midway through the video

Like for AVIGAN, it’s again about RdRA. Turns out Zn2+ ions latch onto the enzyme and act as an inhibitor. [UPDATE: reference here.] The trouble is getting zinc into the cell. Now in a completely unrelated research project on metallophores as anticancer drugs, it was found that chloroquine is a very good zinc ionophore: https://doi.org/10.1371/journal.pone.0109180

I doubt it is the most effective of the three. On the other hand, chloroquine and its less toxic close relative hydroxychloroquine have been used extensively for decades in areas where malaria is endemic, both for treatment and prophylaxis, so their safety profile and side effects are very well understood. Besides they are very cheap as well. (Report of stocks running out in Western countries: well, these aren’t drugs you routinely stockpile unless you are dealing with malaria all the time… although they have been in some use for lupus and rheumatoid arthritis.) So it apparently has been part of treatment regimes in both Korea (hydroxchloroquine) and China, and it appears to at least some extent in Italy.

Speaking of Italy: yesterday the independent media circulated a report that only 1% of case fatalities in Italy were people without pre-existing conditions. Meanwhile, Bloomberg has picked up the story, and from there I located the original official report (in Italian) on the website of the Italian public health office. This graph is from the Bloomberg report:

and this table (screenshot) comes from the original report

Table 1 from the Italian March 17 report:pre-existing conditions in patients deceased from coronavirus

The Italian names mean, in order, coronary disease, atrial fibrillation, stroke, hypertension, diabetes, dementia, COPD (chronic obstructive pulmonary disease), active cancer in the past 5 years, chronic liver disease, and chronic kidney insufficiency. Needless to say, the statistical risk for ALL of these increases with age, so as patients get older, the percentage of them without any comorbidities will get smaller and smaller.

Stay well, stay safe, and above all, stay calm and rational.

UPDATE: Teva Pharmaceuticals donates 6 million doses of hydroxychloroquine.
And a commenter on Facebook drew my attention to this French clinical trial that just got published (open access PDF here). Especially in combination with azithromycin (presumably for secondary infection prophylaxis), results look very promising.

COVID-19: interesting data from Korea and from the Diamond Princess

One of the first countries to deal with the epidemic was South Korea. Unlike China, South Korea is a fairly transparent society and data published by the Korean CDC (Center for Disease Control) can be more or less taken at face value.

A progress report is published every day on their website: here is today’s edition.

The most interesting part of the report is Table 5, which I am reproducing as a screenshot below:

Table 5 from the Korean CDC report, March 18, 2020

Let’s have a good look at this. Preliminary remark: Korea started a massive testing (according to Table 1 in the same report, nearly 300,000 people have been tested, at a current rate of 10,000 a day) and tracking program early, leveraging all available tech data — privacy concerns be darned.

Observation 1: overall mortality is 1 (one) percent. Still one percent too much, to be sure. But considerably lower than what has been reported from some other places — I suspect because of undertesting.

Observation 2: mortality in the 0-29 age bracket is nil — not one death out of 2,867 patients.

Observation 3: in the 30-49 age bracket, just two (2) deaths out of 2,044 patients, or about 0.1%. Only above 50 does mortality start rising, over 60 in a worrisome fashion. (Not coincidentally, so do comorbidities/pre-existing conditions. I would love to see the statistics broken down between otherwise healthy people and those with chronic cardiovascular/pulmonary/immunity/diabetes problems, or cancer patients. Hypertension is apparently another major risk factor.)

Observation 4: Note the interesting “gender gap”. Men (1.39%) have nearly twice the mortality of women (0.75%). I asked friends on Facebook familiar with South Korea, and they told me over half of men smoke, compared to fewer than five percent of women.

Now what can we expect for older people who are otherwise healthy? Chinese data (caveat lector) suggest overall mortality for patients without comorbidities may be about one-third the overall statistic. https://www.worldometers.info/coronavirus/coronavirus-age-sex-demographics/

And then there is the uncertainty factor of how many people are asymptomatic virus carriers. This is impossible to ascertain without a much more massive testing program (and this isn’t a test you can quickly do with a strip!), but I have seen estimates from 5-7 carriers for each overt disease case.

But the Diamond Princess cruise ship offers an interesting insight. It had nearly 4,000 people on board—many of them in risk groups. (Somebody who used to perform aboard cruise ships quipped that passengers are mostly “the newlywed and the nearly dead” ;)) You’d expect these packed together on a ship in quarantine to be all infecting each others. And yet… 4,061 passengers and crew were examined, on board what effectively became an unintentional virus incubator. Only 712 contracted the virus (about 17.5%), of which 334 asymptomatic (8.2% of the total), leaving 378 (9.3% of the total) ill. Only 7 people died (1.85% of those ill, or 0.17% of all passengers and crew examined), all of them age 70 or older. (Remember, the passenger population is skewed toward the elderly.)

One might treat Diamond Princess stats as an upper limit (since spreading in even dense urban areas will never be as efficient as on a cruise ship) and South Korea as what can be achieved with agile and efficient tracking and containment measures.

Meanwhile, a frantic search for both vaccines and drugs continues. One track that may yield results earliest is the repurposing of existing drugs following off-label testing, since safety and “therapeutic interval” testing have already been done for their original approval. I have mentioned a promising remdesivir trial and I see increasing reports that chloroquine (which has been used for decades as an antimalarial) may interferewith the virus lifecycle. (See e.g., https://www.ncbi.nlm.nih.gov/pubmed/32171740)

Be well, stay healthy, be prepared, and remember:

[L]et me assert my firm belief that the only thing we have to fear is fear itself — nameless, unreasoning, unjustified terror which paralyzes needed efforts to convert retreat into advance.

FDR, inaugural address (1933)

UPDATE: via Behind The Black,

(1) an article in SCIENCE about South Korea and how it got a “wake-up call” in 2015 when a businessman brought back MERS from the Middle East

(2) a lengthy analysis of the Diamond Princess data
(3) are there 6 asymptomatic or “too mild to notice” cases for each clinical case?

(4) https://www.statnews.com/2020/03/16/lower-coronavirus-death-rate-estimates/

UPDATE 2: computational biochemistry pioneer Michael Levitt (2013 Nobel Prize in Chemistry shared with Arieh Warshel and Martin Karplus) sounds an optimistic note based on what he knows. His comments start off with Israel (he divides his time between Weizmann and Stanford) but then go on to the rest of the world.