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: 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.