COVID19 update, June 21, 2020: Current understanding of clinical features; vitamin D finally hitting the UK media

Very briefly after a long workday.

Dr. John Campbell summarizes our current understanding of clinical features:

 

 

And again Dr. John Campbell on vitamin D finally hitting the media in the UK

 

 

Finally, a brief video from the Israeli news channel (in Hebrew) about the latest COVID19 testing facility coming online, set up by the MyHeritage.com human genetics company with a Chinese partner (a spokesperson of whom speaking briefly in English). Located in the central town of Petach Tikva, it can process 10,000 samples per day in batches of 96.

ADDENDUM: seems New Zealand’s claim of having eradicated the virus (with an official count of zero active cases) was a little premature. (Via Instapundit.)

And (hat tip: Erik W.) The Gold Opinion, a blogger who is both an emergency physician and  a lawyer, on how hydroxychloroquine became a political football, not just in the political arena but (sadly) in medical journals. Read the whole thing.

COVID19 update, June 11, 2020: vitamin D as “the low-hanging fruit of the epidemic”; deficiency statistics for Israel; first monoclonal antibody for COVID19 enters clinical trials

(1) John Campbell and Roger Seheult both again have videos on vitamin D

Apparently, the French medical academy now also got in on the act. Adapted from his notes: There is a significant correlation (95.4% confidence) between vitamin D deficiency and mortality from COVID-19. This phenomenon follows a North-South gradient, but Nordic countries are the exception, as foods there are routinely fortified with vitamin D (since the long subarctic winter otherwise causes major problems).  Spain and Northern Italy have counterintuitively high rates with vitamin D deficiency, as they do not normally fortify foods nor take supplements.

 

 

Now I got curious about Israel with its sunny climate, and found this in the IMAJ (Israel Medical Association Journal)

(journal issue from the publisher) (ResearchGate entry for paper)

 

As you can see in Table 3 (screenshotted below), there is a difference between Ashkenazi Jews (i.e., those whose ancestors came from Central and Eastern Europe), non-Ashkenazi Jews (in Israeli public discourse, actual Sephardim — descendants of the Spanish Expulsion — are commonly lumped in with Yemenite, Iraqi, Iranian,… Jews who descend from their own Diaspora branches), and Israeli Arabs. While there are some quite swarthy Ashkenazi Jews (as in: swarthy enough to pass for Arab), and conversely there are non-Ashkenazi Jews and Arabs who are quite light-skinned, the difference between the population averages is quite obvious. And indeed, this is reflected the vitamin D deficiency statistics below. Even with the small sample, statistics are significant at the 95% or more level.

Table 3 upper

Now elderly people of any ethnicity have more vitamin D deficiencies to begin with. So what is the sample is narrowed down to people aged between 20 and 50? That’s the lower pane of that table:

 

Table3 lower

Look, it’s a trade-off. Darker skin means you can spend more time outdoors in sunny climates without getting sunburned (the origin of the term “redneck”) or (G-d forbid) developing skin cancer. But it does make you more at risk  for vitamin D deficiency — and all that entails for the immune system —  if you live at northern(-ish) latitudes and/or spend most of your time indoors.

And you just have to stick the title of this paper in Google Scholar and look at the papers citing it to see a pile of studies linking vitamin D deficiencies with adverse outcomes for all sorts of illnesses. 

Medscape referred to vitamin D as “the low-hanging fruit of the epidemic”. It sure is.

 

(2) Chemical and Engineering News reports  that Eli Lilly has started phase 1 clinical trials with a monoclonal antibody. 

The discovery effort began at the end of February. Now, just 3 months later, Lilly says it has given the experimental antibody, called LY-CoV555, to the first participants in a Phase I clinical study of people hospitalized with COVID-19. The trial began more than a month ahead of the companies’ earlier goal of late July.

The 90-day turnaround from discovery to injection is likely a record for monoclonal antibody drug development. LY-CoV555 may also be the first experimental drug designed after the discovery of SARS-CoV-2 to be tested as a treatment for COVID-19. The dozens of therapies already tested in COVID-19 patients—including remdesivir, an antiviral made by Gilead Sciences—were discovered before the pandemic and are now being repurposed to fight the coronavirus.

LY-CoV555 targets the spike protein of SARS-CoV-2 and in preclinical studies prevented the virus from infecting human cells. Scientists hope that mass-producing these antibodies will help clear the virus from people who are already infected and struggling to recover. Antibodies could also be given to healthy people to help prevent an infection for a few weeks or months. That prophylactic approach could prove useful for high-risk people, including those with compromised immune systems and medical workers who face frequent exposure to the virus. […]

LY-CoV555 targets the spike protein of SARS-CoV-2 and in preclinical studies prevented the virus from infecting human cells. Scientists hope that mass-producing these antibodies will help clear the virus from people who are already infected and struggling to recover. Antibodies could also be given to healthy people to help prevent an infection for a few weeks or months. That prophylactic approach could prove useful for high-risk people, including those with compromised immune systems and medical workers who face frequent exposure to the virus.

Lilly’s program is one of about two dozen underway to develop monoclonal antibodies that target SARS-CoV-2. Several other firms, including Regeneron and Vir Biotechnology, expect to begin clinical trials of their antibodies in June or July.

The main goal of Lilly’s Phase I clinical trial is to see if LY-CoV555 is safe, but the company is taking the unusual step of including a placebo group in the study. That could provide early signs of whether the drug is working. Lilly says that it expects results by the end of June and that it will begin a larger, Phase II trial soon after if the drug appears safe.

Lilly has already begun large-scale manufacturing and is working on having several hundred thousand doses ready by the end of the year.

The discovery effort began Feb. 25, when AbCellera received a plasma sample obtained from a person who had been infected with SARS-CoV-2 and had recovered. That plasma contained precious B cells—the antibody factories of our immune systems. AbCellera scanned through more than 5 million B cells to find ones that made antibodies targeting the SARS-CoV-2 spike protein.

 

(3) Both masgramondou and a friendly writer sent me links to this article in al-Grauniad (https://archive.is/lkKN0) I am glad to see that exasperation at repeated “coat-turning” on lockdown and social distancing measures is not just the province of political conservatives and libertarians. 

 

 

COVID19 update, May 23, 2020: CDC dramatically revises fatality rates downward; important new immunity data and “cross-reactivity”

 

(1) Pardon my French, but this is a big [bleep]ing deal. Via Matt Margolis, here are revised CDC best estimates for COVID-19 epidemiological parameters (Table 1, “Scenario 5”). Parameter values are based on data received by CDC prior to 4/29/2020

Their R0=2.5 (remember, R-naught is the reproductive number absent any intervention). Percent asymptotic infections is 35%. 

Age cohort  Fatality  Hospit.  of which ICU 

Under 50 0.05% 1.7% 21.9% 

50-64 0.2% 4.5% 29.2%

Over 65 1.3% 7.4% 26.8%

Overall 0.4%  3.4% N/A 


Also according to the report, about three-quarter of patients in the ICU need mechanical ventilation of some sort, regardless of age group.

Now wait a second, you say. According to worldometers, the cumulative documented infections on April 29 were 1,064,194, with 61,655 deaths. That’s an overt case fatality rate (CFR) of 5.79% — while now CDC is talking a CFR of 0.4% CFR, and an infection fatality rate of 0.26% [that is, 0.4%*(100%-35%)]. How come?

Well, “overt” or “documented” is the operative word here. These number imply a Dunkelziffer/undocumented infection rate of about 22 times the known infection rate. (This ratio is actually within the uncertainty band of the revised Santa Clara County community sampling study. (Bendavid, Ioannides et al. from Stanford).

As I reported here on May 5, German virologist Hendrik Streeck, from his whole-community testing of the hard-hit German town of Gangelt, inferred an IFR of “0.36%, but possibly as low as 0.24%”. He at the time suggested the ratio between the overt CFR and 0.36% as a guesstimate for the Dunkelziffer. It increasingly looks like Streeck, Ioannides, and the CDC are all on the same page to within overlapping uncertainties.

 

Back in March, the single biggest “known unknown” the decision makers had was precisely the Dunkelziffer. Would they have decided on hard lockdowns based on a 0.26% IFR? Chances are, many countries would have hewn a course closer to Sweden’s. But decisions made “in the fog of war”, as a member of our local ad hoc planning commission described it, are easy to second-guess with 20:20 hindsight. Back then, our own commission applied case fatality rates by age cohort reported from China to our much “younger” population pyramid, and arrived at an “if we do nothing” back-of-envelope upper limit 20,000 dead before herd immunity would be reached. Based on  what we know with benefit of hindsight, it would probably have been more in the 3,000-8,000 range. As of today, after a strict but comparatively brief lockdown and a phased reopening, we have fewer than 300 dead out of a population of 9.15 million. So it is possible that the lockdown saved thousands of lives here — but it could be that our thankfully small mortality is thanks as much to our sunny climate and comparatively outdoors lifestyle as to any human intervention.

What we can tell now, however, is that extended lockdowns have long outlived any epidemiological purpose they ever might have had. At this point, their collateral mortality will well exceed any residual epidemiological benefit they might still have. Besides, in the states and countries that have reopened, the sky isn’t falling.

(2) This new paper in the top-tier journal CELL https://doi.org/10.1016/j.cell.2020.05.015 (h/t: LittleOldLady) and this press release about it, in layperson-friendly languagee (h/t: Jeff Duntemann) have some very hopeful  news about COVID19 and immunity. But the big shocker to me was buried further down:

The teams also looked at the T cell response in blood samples that had been collected between 2015 and 2018, before SARS-CoV-2 started circulating. Many of these individuals had significant T cell reactivity against SARS-CoV-2, although they had never been exposed to SARS-CoV-2. But everybody has almost certainly seen at least three of the four common cold coronaviruses, which could explain the observed crossreactivity.

It is still unclear, though, whether the observed crossreactivity provides at least some level of preexisting immunity to SARS-CoV-2 and therefore could explain why some people or geographical locations are hit harder by COVID-19.

“Given the severity of the ongoing COVID-19 pandemic, any degree of cross-reactive coronavirus immunity could have a very substantial impact on the overall course of the pandemic and is a key detail to consider for epidemiologists as they try to scope out how severely COVID-19 will affect communities in the coming months,” says Crotty.

 

Most common colds are caused by rhinoviruses, but actual coronaviruses account for a minority of them. “Cross-reactivity” is immunology-speak for where exposure to one antigen results in at least a partial immune response to related antigens. What Edward Jenner achieved — inoculating people with the relatively innocuous cow pox and thus giving them immunity to the far more dangerous smallpox — is an example of strong cross-reactivity. [*] Hmm, could be be seeing inoculation with common-cold coronaviruses?

Staying on the immunity topic, reader Cathe Smith drew my attention to this recent paper in NATURE Communications: https://doi.org/10.1038/s41467-020-16505-0 Let me just give a teaser:

To address the urgent need for a medical countermeasure to prevent the further dissemination of SARS-CoV-2 we have employed a synthetic DNA-based vaccine approach. Synthetic DNA vaccines are amenable to accelerated developmental timelines due to the ability to quickly design multiple candidates for preclinical testing, scalable manufacturing of large quantities of the drug product, and the possibility to leverage established regulatory pathways to the clinic. Synthetic DNA is temperature-stable and cold-chain free, important features for delivery to resource-limited settings7. Specifically for the development of a COVID-19 vaccine candidate, we leveraged prior experiences in developing vaccine approaches to SARS-CoV8, and our own experience in developing a MERS-CoV vaccine (INO-4700)9,10, as well as taking advantage of our vaccine design and manufacturing pathway previously utilized for the Zika vaccine candidate, GLS-570011, which was advanced to the clinic in under 7 months. INO-4700 and GLS-5700 vaccines are currently in clinical testing.

 

 

 

[*] Cross-reactivity is not limited to pathogens. People who have an allergic reaction to a given antibiotic (e.g. a penicillin), and who are switched to a different antibiotic (e.g., a cephalosporin) may sometimes develop a cross-reaction to the latter (which is from a different “branch” of the same chemical family, beta-lactams).

ADDENDUM: New CDC report on transmission: easily from person to person, less easily via fomites (intermediate objects), unlikely via pets. John Campbell clarifies.

 

And via Dr. Seheult, an analysis piece in THE LANCET Diabetes and Endocrinology about vitamin D and COVID19. 

https://doi.org/10.1016/S2213-8587(20)30183-2

Moneygrafs:

A growing body of circumstantial evidence now also specifically links outcomes of COVID-19 and vitamin D status. SARS-CoV-2, the virus responsible for COVID-19, emerged and started its spread in the Northern hemisphere at the end of 2019 (winter), when levels of 25-hydroxyvitamin D are at their nadir. Also, nations in the northern hemisphere have borne much of the burden of cases and mortality. In a cross-sectional analysis across Europe, COVID-19 mortality was significantly associated with vitamin D status in different populations. The low mortality rates in Nordic countries are exceptions to the trend towards poorer outcomes in more northerly latitudes, but populations in these countries are relatively vitamin D sufficient owing to widespread fortification of foods. Italy and Spain are also exceptions, but prevalence of vitamin D deficiency in these populations is surprisingly common. Additionally, black and minority ethnic people—who are more likely to have vitamin D deficiency because they have darker skin—seem to be worse affected than white people by COVID-19. For example, data from the UK Office for National Statistics shows that black people in England and Wales are more than four times more likely to die from COVID-19 than are white people.

[…]
Rose Anne Kenny (Trinity College Dublin, University of Dublin, Ireland) led the cross-sectional study into mortality and vitamin D status and is the lead investigator of the Irish Longitudinal Study on Ageing (TILDA). She is adamant that the recommendations from all public health bodies should be for the population to take vitamin D supplements during this pandemic. “The circumstantial evidence is very strong”, she proclaims regarding the potential effect on COVID-19 outcomes. Adding, “we don’t have randomised controlled trial evidence, but how long do you want to wait in the context of such a crisis? We know vitamin D is important for musculoskeletal function, so people should be taking it anyway”. Kenny recommends that, at the very least, vitamin D supplements are given to care home residents unless there is an extremely good reason not to do so.
Adrian Martineau (Institute of Population Health Sciences, Barts and The London, Queen Mary University of London, UK), lead author of the 2017 meta-analysis has joined with colleagues from universities around the UK to launch COVIDENCE UK, a study to investigate how diet and lifestyle factors might influence transmission of SARS-CoV-2, severity of COVID-19 symptoms, speed of recovery, and any long-term effects. They aim to recruit at least 12 000 people and to obtain interim results by the summer. Despite his enthusiasm for the study, Martineau is pragmatic: “At best vitamin D deficiency will only be one of many factors involved in determining outcome of COVID-19, but it’s a problem that could be corrected safely and cheaply; there is no downside to speak of, and good reason to think there might be a benefit”.
 

And now Dr. Anthony Fauci has warned that staying closed for too long could cause irreparable damage.

COVID19 update, May 22, 2020: the human immune system; unlocked but the sky isn’t falling; professional courtesy; remdesivir study update

Derek Lowe wonders if there may be a unique COVID19 immune response. In the process, he gives a nice overview of the human immune system.

The NIH discontinued its double-blind remdesivir study. Mind you, not because the drug isn’t working, but because it is working substantially better than placebo controls, and they concluded that it was unethical to continue to feed patients placebos when they had a (somewhat) working drug on hand. Related.

Attacking  COVID19 from every angle, including molecular modeling on large-scale high-performance computing facilities.

Certain media outlets that cannot bring themselves to empathize with small business workers and owners who see their income dwindle to zero can somehow wax tearful about the plight of “sex workers” during the pandemic. Instapundit snarks:

“THE PRESS HAS SYMPATHY FOR SOME PEOPLE WHO ARE OUT OF WORK: The Fragile Existence of Sex Workers During the Pandemic. Sympathy for prostitutes, though, is probably just a species of professional courtesy.”

President Trump says he won’t close the country again if a second wave of coronavirus hits. Actually, this is probably sensible. The first closure was done in a “fog of war” situation. Now we understand a bit more about the epidemic and especially about what it is not

A study by a JP Morgan analyst reportedly shows that COVID-19 infection rates are declining in states that lifted lockdowns. I haven’t seen the original, but Georgia and Florida have been open for a while now and the sky hasn’t fallen on them. (Did it move sideways? Porcupine Tree fans can’t help asking.) 

 

But as a sanity check, here is a list of countries in Europe and the Middle East that have started opening a while ago and still (click on the names for Worldometer links) have nicely trending-down active case numbers:

 

ADDENDUM: Mike Hansen MD on vitamin D

 

 

 

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, May 19, 2020: scaling up drug production; super-spreading events; reopening churches and synagogues; Matt Ridley on vitamin D

(1) OK, so you have an experimental coronavirus drug and suppose it actually works — what next? NATURE has an article on the challenges involved in scaling up production to massive quantities. For instance, Gilead, having donated its entire supply of drug on hand, has now licensed production to five generics manufacturers.
And like with other manufactured products, the switch to “lean” “just in time” manufacturing and the outsourcing of critical components to cheap specialized suppliers abroad creates vulnerabilities. (The article gives a non-Chinese example: following the Fukushima earthquake and tsunami, the pharmaceutical industry faced a shortage of polyethylene glycol, as all major suppliers of this chemical were in Japan.)

(2) According to an analysis by the London School for Hygiene and Tropical Medicine, super-spreader events may be responsible for 80 percent of more of COVID19 cases, reports The Daily Telegraph.

“As most infected individuals do not contribute to the expansion of an epidemic, the effective reproduction number could be drastically reduced by preventing relatively rare superspreading events”[…] Hospitals, nursing homes, large dormitories, food processing plan[t]s and food markets have all been associated with major outbreaks of Covid-19.

Vigorous physical activity in an indoor space without adequate ventilation is one risk factor, as a South Korean analysis of outbreaks at intense workout classes at gyms found. Less strenuous classes, such as yoga, were not associated with such outbreaks, nor were outdoor sports.

Singing at high volume, and the attendant voice projection[*], is another factor associated with super-spreading events:

In Washington State on the west coast of America, a church choir went ahead with its weekly rehearsal in early March even as Covid-19 was sweeping through Seattle, an hour to the south. Dozens of its members went on to catch the virus and two died. [par] The Washington singers were not the only choristers to be hit. Fifty members of the Berlin Cathedral Choir contracted the virus after a March rehearsal, and in England many members of the Voices of Yorkshire choir came down with a Covid-like disease earlier this year. [par] A choir in Amsterdam also fell victim to the virus, with 102 of its 130 members becoming infected after a performance. One died, as did three of the chorister’s partners.

I’ve already mentioned carnival celebrations in Germany, with everybody kissing everybody and hollering at each other in packed beer halls to be understood over the loud ‘music’. (Outdoor beer gardens are probably safe, if you don’t share steins.) And then there are the apres-ski parties that have become a by-word:

Hundreds of infections in Germany, Iceland, Norway, Denmark and Britain have been traced back to the resort of Ischgl in the Tyrolean Alps. Many had visited the Kitzloch, a bar known for its après-ski parties. [par] The bar is tightly packed and famous for “beer pong” – a drinking game in which revellers take turns to spit the same ping-pong ball into a beer glass. [par] Earlier this year The Telegraph obtained a video from inside the Kitzloch. It may yet come to define the perfect superspreader event, with attendees all singing along to AC/DC’s Highway to Hell

Had I written the latter detail in a novel, an editor would consider it a particularly cheesy foreshadowing technique.

But here is the good news from all of the above: none of it is representative of how one goes about one’s normal daily business.

(3) Prayer without singing returns to synagogues in Germany and Israel (h/t: Mrs. Arbel). Church services in Germany actually reopened a couple of weeks ago: aside from social distancing similar to what is described below for synagogues, no singing.
I had a look at the website of the Zentralrat der Juden in Deutschland (Central Council of Jews in Germany): they actually have a section with COVID19 guidelines. My abridged translation:

* public prayer and Torah reading are allowed again
* people with even mild symptoms should stay away
* maintain a distance of 1.5m (read: 5ft), preferably 2m (6.5ft)
* it is recommended to keep attendance lists in case contacts need to be traced
* if need be to maintain distance, use the largest hall or sanctuary available rather than a small chapel (as many congregations use for regular services)
* no handshakes, hugs, kisses
* worshipers are urged to wear masks (regular day-to-day nonsurgical masks OK)
* recommended to bring your own siddur (prayer book) and, on the Sabbath, chumash (book with the Torah and commentaries)
* using only one’s personal kippa/yarmulke/skullcap and tallit/prayer shawl (and, for weekday morning minyan, tefillin/phylacteries)
* doorknobs etc. are to be disinfected frequently
* disinfectant should be on hand
* no kissing of religious objects (e.g., mezuzah, Torah scroll) — therefore, usual Torah scroll procession before the reading off the menu
* no touching the Torah scroll when called up for a reading[NB: these behaviors are customs and not Jewish law]

(4) Matt Ridley Ph.D., veteran popular science writer and editor[**], lays out the evidence on vitamin D. As usual, his writing is a paragon of clarity.

[M]any people are deficient in vitamin D, especially at the end of winter. That is because, uniquely, vitamin D is a substance manufactured by ultraviolet light falling on your skin. You can get some from fish and other foods, but not usually enough. So most people’s vitamin D levels fall to a low point in February or March when the sun has been weak and its UV output especially so. Public health bodies have long advised people to supplement vitamin D in winter anyway. The level falls especially low in people who stay indoors a lot, including the elderly, and in those who have darker skin. Whereas the safe level of vitamin D is generally agreed to be above 10 nanograms per millilitre, one recent study of South Asians living in Manchester found average levels of 5.8 in winter and 9 in summer: too low at all times of the year. Darker skin reduces the impact of sunlight; so does the cultural habit of veiling; and so does a reluctance among some Muslims to take supplements that might have pork-derived gelatin in them.Vitamin D deficiency has long been known to coincide with a greater frequency or severity of upper-respiratory tract infections, or colds. That this is a causal effect is supported by some studies showing that vitamin D supplements do reduce the risk of such infections. These studies are not without their statistical flaws, so cannot yet be regarded as certain, but they are not quackery like a lot of the stuff coming out of the supplements industry: they come from reputable medical scientists.

What about vitamin D and Covid in particular? Results are coming in from various settings and the main message seems to be that vitamin D deficiency may or may not help to prevent you catching the virus, but it does affect whether you get very ill from it. One recent study in Chicago concluded that its result ‘argues strongly for a role of vitamin D deficiency in COVID-19 risk and for expanded population-level vitamin D treatment and testing and assessment of the effects of those interventions.’ The bottom line is that an elderly, overweight, dark-skinned person living in the north of England, in March, and sheltering indoors most of the time is almost certain to be significantly vitamin D deficient. If not taking supplements, he or she should be anyway, regardless of the protective effect against the Covid virus. Given that it might be helpful against the virus, should not this advice now be shouted from the rooftops? A new article by a long list of medical experts in the BMJ cautiously agrees, confirming that many people in northern latitudes have poor vitamin D status, especially in winter or if confined indoors, and that low vitamin D status ‘may be exacerbated during this COVID-19 crisis by indoor living and reduced sun exposure’.

Read the whole thing. I’ve been taking vitamin D and zinc supplements since the beginning of the crisis, even though I live in sunny Israel and have a very light skin type.

(5) This cartoon from Die Welt probably does not require translation:

[*] full disclosure: I am married to a classical soprano. She can easily fill a hall with sound without a microphone — and one does not achieve that feat without some serious air pressure.

[**] and member of the House of Lords, as the 5th Viscount Ridley

COVID19 update, May 15, 2020: interview about German meat processing plants; Santa Clara County immunology study redux

(1) Die Welt (in German) interviewed a Polish guest worker at a German meat processing plant on condition of anonymity. (The interview was conducted in Polish.)
My summary in bullet points:

  • almost all line workers are Polish, Romanian, and Bulgarian guest workers hired via subcontractors. No German wants to do that work [and definitely not at that salary]
  • we get paid net EUR 6.50 to 9.50 per hour, depending on position. We typically work 12 hours a day, 6 days a week. No bonuses for overtime or weekend work—don’t understand my work contract so I don’t know if I’m entitled. [I’m reminded of the Israeli situation where direct employees of a large enterprise — especially long-standing ones — have lavish benefits, but outsourced subcontractor employees often have none at all.]
  • we work as many hours as we can so we can send more money home
  • we typically live 2 or even 4 to a room in houses or apartments, typically arranged via the subcontractor. I paid EUR 150/mo. for effectively half a room; meanwhile I learned two bits of German so I was able to rent a place for just myself. We kept our place clean, but some of the Bulgarians and Romanians are withheld EUR 250/mo. from their wages for 4-to-a-room pigsties.
  • [He claims] some of the Romanians and Bulgarians can’t read or write in any language, and are hence taken advantage of by the middlemen.
  • “we could never in our lives keep 1.5m/5ft distance on the assembly line.” (Title of the article.) “Our stations are 60cm/2ft apart.” They would have to make the line 2.5 times as long for the same productivity.
  • Contrary to claims in the media, general hygiene in the plant is good; otherwise, there are disinfectant stations at toilets, cloakrooms, entrances.
  • we get fresh cloaks every day, with an RFID tracking chip inside. We ourselves have to carry RFID on our persons. Cloak not returned on end of shift — 30 Euro docked from pay
  • masks are mandatory inside now; they used to be optional, but most were wearing them anyhow
  • German foremen are generally polite and reasonable, since previous incidents of brutality led to walkouts
  • Poland just exempted cross-border commuters from 14-day quarantine, so I’m looking forward to visiting my family for the first time in 8 weeks.

(2) (Hat tip: Cedar Sanderson). Interview with Prof. John Ioannides about the revised version of the Santa Clara County [read: Silicon Valley] immunity study [below: Bendavid et al.]. You can read the paper for yourself here (note the “v2” for Version Two at the end of the URL: the original is still available by substituting “v1”. These kinds of preprint servers keep full version history to avoid “Oceania has always been at war with Eastasia” rewriting of history):
https://www.medrxiv.org/content/10.1101/2020.04.14.20062463v2

I think pretty much every serious epidemiologist assumes there is a substantial “Dunkelziffer”/stealth infection rate — the debate is about how big. Truly asymptomatic infection proportions? 22% was reported by German virologist Prof. Hendrik Streeck on his all-community test in a German village; Ref.8 of Bendavid et al. reaches 17.9±2.4% from Diamond Princess data. But this excludes “eh, just a seasonal cough/cold” minimally symptomatic cases, which I suspect are the majority of the Dunkelziffer.

In the current manuscript, they arrive at 1.2% seroprevalence after weighing test performance, and 2.8% (95CI 1.3-4.7%) after adjusting for population demographics.


These prevalence point estimates imply that 54,000 (95CI 25,000 to 91,000 using weighted prevalence; 23,000 with 95CI 14,000-35,000 using unweighted prevalence) people were infected in Santa Clara County by early April, many more than the approximately 1,000 confirmed cases at the time of the survey.

In plain English: the original manuscript claimed there were 50 to 85 “stealth” infections for every documented one, while in the revised version, it may be as low as 14 or as high as 91. OK, let’s apply a simple “Streeck sanity check” here: he proposed using the ratio between the reported case fatality rate (CFR) and his whole-population IFR (infection fatality rate) of about 0.36±0.12% as a crude estimate of how many “stealth” infections are out there for every documented one. From Worldometers data today, I get a 4.1% apparent CFR for California, and 5.6% CFR for Santa Clara County. 5.6 divided by 0.36 leads to about 16:1, though it could be as high as 24:1, consistent with Ioannides’s “unweighted prevalence” data and at the lower end of the 95% confidence interval for weighted prevalence.

(3) Via Erik Wingren, nutritionist Dr. Rhonda Patrick on the wildly popular Joe Rogan Show, speaking on how to boost one’s immune system against infections in general (and thus also COVID19). A commenter summatized the segment as “vitamin D, sauna, sauna,…” Here is a more useful table of contents of the 3-hour podcast.

(4) Israel Hayom, lying around in our condo complex’s lobby, had a headline where outgoing Economics minister Moshe Kaḥlon was quoted as saying: “We sacrificed the economy on the altar of health”. It reminds me of the debate in the US about who is right, Anthony Fauci MD or Senator Rand Paul (R-KY; himself an MD ophthalmologist and a COVID19 survivor). My personal answer: both. They just emphasize opposite scales of the balance. There is no perfect solution here—only a trade-off between different sources of mortality, and the best you can do is try to minimize their sum. Because make no mistake: even the now-disgraced Neil Ferguson (he of the “2 million dead” model that ) acknowledged that continued hard lockdown would engender collateral mortality exceeding any reduction in COVID19 mortality.

(5) Lagniappe: Roger Seheult MD on glutathione deficiency, which brings us back to our previous items on N-acetylcysteine, a.k.a. “NAC”.

ADDENDUM: Israel Institute for Biological Research files for patents on 8 SARS-nCoV-2 antibodies

Antibody tests of two Snohomish County, WA residents push back COVID19 timeline in the USA to probably mid-December.

Marta Hernandez on the ChiCom propaganda machine being turned up to 11. But Peter Zeihan has an interesting out-of-the-box theory about that.

COVID19 update, May 10, 2020: more on COVID19 outbreaks at German meat processing plants; BND drops bombshell about China and WHO; miscellaneous updates

(1) COVID19 outbreaks at meat processing plants are not just a US phenomenon anymore. Apropos the report yesterday of large outbreaks at two such plants at opposite ends of Germany (here and here, both articles in German): it was pointed out that many at these plants are foreign workers living in very tight quarters. But in addition, a friend who is a Ph.D. biologist as well as a volunteer EMT responded: “Meat packing is one of those physical jobs (so high respiration rate) which happens in close quarters, in a cool and air[-conditioned] environment. Most other airconditioned environments are probably not so close together and/or do not involve the level of physical labor. The other possible idea is that meat surfaces and the aerosols generated cutting with band-saws might be a good place for the virus to survive and thrive.”

(2) RedState, quoting German weekly Der Spiegel, has a bombshell: The BND (Bundesnachrichtendienst or Federal Intelligence Serivce, Germany’s equivalent of the CIA — in a report that is otherwise critical of Trump— says the following (my translation from the original German):

“Nevertheless, to the BND’s knowledge, China urged the World Health Organization (WHO) at the highest level to delay a global warning after the outbreak of the virus. On 21st January China’s Head of State Xi Jinping, during a telephone conversation with WHO leader Tedros Adhanom Ghebreyesus, asked the WHO to withhold information on human-to-human transmission and to delay a pandemic warning. According to the BND, China’s information policy has resulted in the loss of four to six weeks worldwide to fight the virus.” [*]

Confirmation of what was obvious to many of us.

(3) Miscellaneous updates:

{*] original wording: “Nach Erkenntnissen des BND drängte China die Weltgesundheitsorganisation WHO allerdings nach dem Ausbruch des Virus auf höchster Ebene dazu, eine weltweite Warnung zu verzögern. Am 21. Januar habe Chinas Staatschef Xi Jinping bei einem Telefonat mit WHO-Chef Tedros Adhanom Ghebreyesus gebeten, Informationen über eine Mensch-zu-Mensch-Übertragung zurückzuhalten und eine Pandemiewarnung zu verschleppen. [new paragraph] Nach Einschätzung des BND sind durch die Informationspolitik Chinas weltweit vier bis sechs Wochen für die Bekämpfung des Virus verloren gegangen.”

UPDATE: via masgramondou, a second analysis of Neil Ferguson’s COVID19 model code that is even “better” (ahem) than the first. I’ve encountered enough modeler hubris in my day job that I believe I recognize it when I see it.

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 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 .