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.

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

  1. […] “dark matter”) — as of early June, about 10:1. If this ratio (which is lower than what serological studies elsewhere have indicated) holds true, then as many as 1.2 million Israelis out of 8.67 million, or just shy of 14%, have […]

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