COVID19 update, June 22, 2020: Is the virus weakening from a “tiger” to a “feral cat”?; EU taking a harder stance on China

(1) Italian infectious diseases specialist Prof. Matteo Bassetti, who works at the St. Martin Hospital in Genoa, makes the claim that the virus has mutated into a weaker form, reports the Daily Telegraph (among many other outlets). Here is an archive copy: http://archive.is/1EWSp

Coronavirus has downgraded from a “tiger to a wild cat” and could die out on its own without a vaccine, an infectious diseases specialist has claimed.
Prof Matteo Bassetti, head of the infectious diseases clinic at the Policlinico San Martino hospital in Italy, told The Telegraph that Covid-19 has been losing its virulence in the last month and patients who would have previously died are now recovering.
[…] 
“The clinical impression I have is that the virus is changing in severity,” said Prof Bassetti.
“In March and early April the patterns were completely different. People were coming to the emergency department with a very difficult to manage illness and they needed oxygen and ventilation, some developed pneumonia.
“Now, in the past four weeks, the picture has completely changed in terms of patterns. There could be a lower viral load in the respiratory tract, probably due to a genetic mutation in the virus which has not yet been demonstrated scientifically. Also we are now more aware of the disease and able to manage it.
“It was like an aggressive tiger in March and April but now it’s like a wild cat. Even elderly patients, aged 80 or 90, are now sitting up in bed and they are breathing without help. The same patients would have died in two or three days before.
“I think the virus has mutated because our immune system reacts to the virus and we have a lower viral load now due to the lockdown, mask-wearing, social distancing. We still have to demonstrate why it’s different now.

Wishful thinking? Though this sort of thing has been known to happen in the past. Viruses that kill off their hosts quickly (such as Ebola and MERS) don’t get to spread their genome as well as those who just make their hosts sick, so there is “evolutionary pressure”, if you like. 

[UPDATE: A reader comments: “I don’t remember where I read it, but I recall a journal article from back when I was a bio/pre-nursing major that postulated that no disease with an infection mortality rate above ~5% would ever go global despite air travel, unless artificially spread, or had a crazy long (>1month) incubation period, because any bug that deadly kills enough people that the infected population ends up quarantined almost by default, no matter where. It seemed quite logical to me.”]

There is, of course, another possible explanation. Vitamin D deficiency is surprisingly prevalent in northern Italy, especially in winter. With the summer weather and people again being able to go outside — particularly indulge in the Italian pastime of sitting outside with one’s coffee and/or pasta — people may simply be less deficient and their immune systems better able to face the challenge of the virus.

The proof in the pudding would be to sequence the genome of COVID19 from this putative “new strain” and see if it really is different in anything that would affect the spike, the replicase (a.k.a, RdRp), or another part of the viral machinery. Absent that, my money is on vitamin D.

(2) Die Welt  (in German) reports on unprecedented complications in the relations between the EU and China, in the context of an EU summit meeting in Brussels on the subject.  The misinformation/Fake News campaign to diffuse the regime’s responsibility for the epidemic is one factor, the de facto abolition of Hong Kong’s internal autonomy is another. Then there are the “reshoring” efforts to bring vital production of medical supplies and PPE back to Europe in order not to be dependent on a fragile supply chain.

The article also cites measures to impede hostile takeovers of struggling companies by Chinese state-backed “bargain hunters” . 

They say about pressuring China,  “Trump does it his way, we do it our way, [albeit] less aggressive [sic].” The journalist comments that China has thus far not gotten any significant pushback for its behavior, and that pressure from European side might make them think again.

(3) The American Chemical Society has a special virtual issue on COVID-19 research across its extensive portfolio of research journals in various areas of chemistry, plus (alas) some what I shall charitably describe as “advocacy papers” and opinion pieces. But that still leaves a lot of original research papers: one that jumped out at me was this one about the role of glutathione deficiency (see our earlier blog post)

https://doi.org/10.1021/acsinfecdis.0c00288

ADDENDUM (hat tip: Mrs. Arbel). Dr. Shelton, about 15 minutes into this video, has some advice for people enhancing their vitamin D through sunbathing: “he says after sun exposure don’t shower off the body oils on large body areas … that’s where the vitamin D is still being made for a day …”

COVID19 update, June 19, 2020: Second wave in Israel; Q&A with Dr. Seheult

(1) So it looks like, sadly, we have a real second wave here, with new cases per day now crossing the 300 mark. Unlike in the winter, most of the new cases are kids or young people for whom the disease is usually not life-threatening, and our hospitals are doing fine for ICU capacity thanks to the earlier scramble to set up new “machlakot keter” (lit.: ‘crown departments’) at the various hospitals. Healthcare officials are basically saying, “we’re ready” rather than “the sky is falling”.

In part thanks to that, presumably, it appears officials have decided that the cost of a second lockdown, both economically and in terms of collateral damage to human life, will exceed any benefit, and that therefore we’re staying open.

 

Below is a graph from the new, and highly informative, COVID19 data dashboard of the health ministry. Male in blue, female in green, population pyramid is the fuzzy background, the focused bars are the age distribution of active cases. 

(2) this Q&A section with Roger Seheult MD is long but highly informative. 

 

 

More later… Shabbat shalom…

COVID19 update, May 28, 2020: ACE inhibitors beneficial; asymptomatic infection rate as high as 80%; NYT on California economy in freefall

(1) The lead story of Chemical and Engineering News, the house organ of the American Chemical Society, is about rethinking the role of ACE inhibitors (angiotensin converting enzyme inhibitors, a commonly used family of blood pressure drugs).

https://cendigitalmagazine.acs.org/2020/05/22/rethinking-the-role-of-blood-pressure-drugs-in-covid-19/content.html

“Once thought to boost levels of ACE2 , the novel coronavirus’s doorway into human cells, these widely used medicines are now contenders to treat the respiratory disease”

(2) Meanwhile,  the Daily Telegraph has a popular write-up of an intriguing paper that just appeared in Thorax, a daughter journal of the British Medical Journal. It suggests the asymptomatic infection rate may be much higher than the 35% in the revised CDC figures

http://doi.org/10.1136/thoraxjnl-2020-215091

ABSTRACT: We describe what we believe is the first instance of complete COVID-19 testing of all passengers and crew on an isolated cruise ship during the current COVID-19 pandemic. Of the 217 passengers and crew on board, 128 tested positive for COVID-19 on reverse transcription–PCR (59%). Of the COVID-19-positive patients, 19% (24) were symptomatic; 6.2% (8) required medical evacuation; 3.1% (4) were intubated and ventilated; and the mortality was 0.8% (1). The majority of COVID-19-positive patients were asymptomatic (81%, 104 patients). We conclude that the prevalence of COVID-19 on affected cruise ships is likely to be significantly underestimated, and strategies are needed to assess and monitor all passengers to prevent community transmission after disembarkation.

The Uruguayan Ministry of Health provided on board SARS-CoV-2 virus testing of all passengers and crew, which occurred on 3 April (day 20; Atgen-Diagnostica, Montevideo) with CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel.

In the body text we find that: 

 

[The 128 who tested positive on RT-PCR]  included all passengers who tested negative on the VivaDiag qSARS-CoV-IgM/IgG Rapid [antibody] Test. There were 10 instances where two passengers sharing a cabin recorded positive and negative results.

[…]

From the departure date in mid-March 2020 and for the next 28 days, the expedition cruise ship had no outside human contact and was thus a totally isolated environment in this sense. […]

[…]

We conclude from this observational study that

• The prevalence of COVID-19 on affected cruise ships is likely to be significantly underestimated, and strategies are needed to assess and monitor all passengers to prevent community transmission after disembarkation.
• Rapid  [antibody] COVID-19 testing of patients in the acute phase is unreliable.
• The majority of COVID-19-positive patients were asymptomatic (81%).
• The presence of discordant COVID-19 results in numerous cabins suggests that there may be a significant false-negative rate with RT-PCR testing. Follow-up testing is being performed to determine this.
• The timing of symptoms in some passengers (day 24) suggests that there may have been cross contamination after cabin isolation.

 

Just how reliable is RT-PCR really?  According to this piece in IEEE Spectrum, current test setups reach are essentially 100% sensitive (no false negatives) and 96% specific (4% false positives) with lab-generated samples., i.e., if you feed them virus cultures. The trouble begins when you have to collect specimens from actual patients.  According to this piece in MD Magazine,   “Of the specimens collected [from known COVID-19 patients], bronchoalveolar lavage fluid specimens demonstrated the highest positive rates of at 93% (n = 14). This was followed by sputum at 72% (n = 75), nasal swabs at 63% (n = 5), fibrobronchoscope brush biopsy at 46% (6/13), pharyngeal swabs at 32% (n = 126), feces at 29% (n = 44) and blood at 1% (n = 3). The authors of that study pointed out that testing of specimens from multiple sites may improve the sensitivity and reduce false-negative test results.” 

 

(3) Via David Bernstein: the WSJ on New York’s long road to recovery even after a lifting of the lockdown. (Archived copy here.)

And via Instapundit, the NYTimes on The price of a lockdown: economic freefall in California

(archived copy ) To be fair, the tourism industry would have been bludgeoned with or without a lockdown, as the (proportionally less important) Swedish tourism sector has learned.

But a large part of the rest could have been mitigated, and can still be mitigated, by not going the “37-step reopening over 10 years” route in California.  (Heck, when did The Babylon Bee forget it was a satirical publication?) But — as much as this sickens even the jaded student of history — I suspect that for some politicians, ensuring that the recovery does not happen before November is worth any price…  

 

Finally, to my Jewish readers, happy Shavuot! There will probably not be an edition on the holiday unless breaking developments warrant it.

 

ADDENDUM: an op-ed in The Lancet in defense of prophylactic use of hydroxychloroquine in India.

COVID19 update, May 26, 2020: Sweden revisited; homes for the elderly; new drug on the block

(0) Israel today celebrated its first day with zero new cases.

(1) Via Instapundit, SSRN (Social Science Research Network, a preprint server similar to arXiv.org, medrxiv.org, biorxiv.org and chemrxiv,org) has a article in press about the Swedish COVID19 epidemic. 

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3609493

Their per capita death rate is an order of magnitude larger than neighboring Scandinavian countries. It is tempting to attribute all this to Sweden’s Sonderweg (“road alone”) — but this article makes a case that at least part results from factors unrelated to Sweden’s decision not to go on lockdown.

Not only is half of Sweden’s mortality concentrated in just the capital city Stockholm, but over 70% of Sweden’s mortality is in nursing homes. As the article explains, in Sweden the elderly tend to stay at home for as long as possible, assisted by home helpers assigned by the public healthcare system. (Independent assisted living facilities do exist, apparently mostly in the private sector.) But normally a home for the elderly is a last-resort option, and those who move in there are generally so frail that their median stay there is under one year. (Such facilities in Sweden have doctors etc. on site.)

Now in a facility where everybody needs a lot of hands-on care, there is plenty of room for nosocomial (i.e., caregiver-transmitted) infections unless staff is (a) healthy and (b) has extensive training and/or experience in biosafety. Guess who does the most “hands-on” work at such care homes? First-generation immigrants from the Third World, often with at best high school education. And guess what else? Immigrants are the second most common group of COVID19 victims in Sweden, after the elderly. 

Immigrants tend to live in crowded conditions, and many probably have  major issues with vitamin D deficiency (and hence a weakened immune system) in winter. (Even light-skinned “Vikings” would be in trouble in a sub-arctic winter, were it not that Scandinavians tend to fortify their diet with vitamin D supplements — I was floored once to see cod liver oil at a hotel breakfast buffet!)

Intriguingly, overall year-over-year mortality is not as elevated as you might expect — COVID19 mortality was compensated in part by an unusually mild flu season.

Now Sweden is just an egregious example of a general trend: Steve “Vodkapundit” Green points out that  42% of Americans whose deaths have been attributed to COVID-19 were in nursing homes or assisted living centers. 

He links to a report of the International Long-Term Care Policy Network about deaths in such facilities in a number of countries. A few quotes:

On the 3rd of May there had been 7,844 deaths linked to COVID-19 in Belgium, of these, 4,164 people died in care homes (53%). The report also includes suspected cases and, of the total deaths, 83% of all care home deaths were suspected cases, and only 17% had been confirmed. The reported % of deaths in care homes has increased since the first date these data were published, from 42% on the 11th April to 53% on the 3rd May. The report also contains data on the numbers of care home staff and residents that have been tested since the 10th of April. As of May 3, 88,883 staff were tested, of these, 3% were positive, and of those who tested positive, 72% were asymptomatic. Of the 68,336 residents who had been tested, 7% were positive and of these, 74% were asymptomatic.

[…] In British Columbia[, Canada], counts published by the BC Centre for Disease Control11 on May 1 illustrate a total of 112 deaths as a result of COVID-19, of which 70 (63%) were patients/residents in care facilities, which includes acute care institutions, long-term care homes, assisted and independent living establishments. On that day, there were a total of 2,145 confirmed cases of COVID-19 in the province, of which 260 (12%) were patients/residents in these establishments. 

[…] In Ontario[…] The official report included a total of 1,216 deaths as a result of COVID-19, of which 590 (49%) were residents in long-term care homes.

[…] Quebec is the province with the highest cases and the most deaths related to COVID-19 in Canada. According to the most up-to-date estimates from both governmental and media releases on April 29, a total of 1,859 deaths as a result of COVID-19 occurred in the province, of which 1,469 (79%) were residents in long-term care homes. Tabarnak!

[…] The total deaths in Germany on the 3rd May were 6,649, so deaths in communal settings represent 36% of all deaths (36.5% including mortality of staff in communal settings)24. […]

The first COVID-19 patient in Israel was diagnosed on February 27th and since then the number of confirmed cases has risen to 15,782 (as of April 29th), with 120 in serious condition and 202 deaths. Of the deaths, 65 were long-term care residents (32%).

[…] According to their data of the 3rd May41, the total number of deaths in nursing homes is 16,878, which, according to this source, adds up to 67% of all deaths by COVID-19 in Spain. The greatest number of deaths happened in Madrid (5,828) and Catalonia (3,044). […]

 

 

(2) Via the Jerusalem Post, here is a preprint from the Israel Institute for Biological Research

https://doi.org/10.1101/2020.05.18.103283

indicating that an analogue of Cerdelga (Eliglustat), a drug for the rare metabolic disorder named Gaucher’s Disease, might be a useful broad-spectrum antiviral. From the abstract:

Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.

 

(3) Miscellaneous:

Charlie Martin about YouTube censorship of comments about the “Fifty-Cent Army” (the paid internet commenter brigade of the CCP). 

DIE WELT refers to Angela Merkel’s silence in the face of China’s repression of Hong Kong as “Merkel’s kow-tow”.

Elsewhere, the German paper reports on the “nightmarishly” empty beaches in St.-Tropez on the French Azure Coast. Now any tourist would be welcome — not just the rich and famous — but they aren’t coming. It would seem obvious that tourism is one sector of the economy that was going to get near-fatal blows with or without lockdowns.

According to the Daily Telegraph, remdesivir will be rolled out in the UK for treatment. 

COVID19 update, US Memorial Day edition: meat-packing plants as hotspots around the world; Japan lifts state of emergency; Philippines in longest lockdown anywhere; Robert A. Heinlein for Memorial Day

(1) A reader drew my attention to a COVID19 outbreak in Nobles County, Minnesota — again linked to a meatpacking plant (JBS, in this case). According to a May 12 report from MPR (Minnesota Public Radio), https://www.mprnews.org/story/2020/05/12/latest-on-covid19-in-mn

In southwestern Minnesota’s Nobles County, where an outbreak hit Worthington’s massive JBS pork plant, about 1 in 17 people have tested positive for COVID-19. In mid-April, there were just a handful of cases. On Tuesday, there were 1,291 confirmed cases. The numbers were still increasing, although at a slower rate than in previous weeks. [Ed.: My source adds: now 1,414 positive cases out of a county population of 21,378, about 6.6% or one in fifteen. So far, there have only been 2 deaths.]

The JBS plant shut on April 20 but has partially reopened with expanded hygiene and health monitoring measures.

Similar problems have been reported in Stearns County, where COVID-19 cases tied to two packing plants — Pilgrim’s Pride poultry plant in Cold Spring and Jennie-O Turkey in Melrose — have skyrocketed. An undisclosed number of workers at both plants have tested positive for the virus.

There were about 55 confirmed cases in Stearns County two weeks ago. By Tuesday, confirmed cases had jumped to 1,512.

The Grauniad has more on US meat-packing plants. 

But this is not just a US thing. We noted several outbreaks at meat packing plants in Germany — earlier we offered a translation of an interview with an anonymous Polish worker in one such plant. In brief: work in very close quarters (2ft/60 cm. between stations) in enclosed, air-conditioned spaces; the line laborers are mostly guest workers (there from Poland, Romania,…) who sleep two to a room or even four to a room in “accommodation” arranged via the subcontractor; … 

And Australia had an outbreak near Melbourne (hat tip: Wannita F.)

 

(2) Japan is apparently lifting its state of emergency even in Tokyo, 

In contrast, the Philippines has been under possibly the longest lockdown anywhere, longer even than Wuhan reports DIE WELT. which also quotes President/strongman Duterte as saying quarantine violators should be shot.Here is a drier report in English in US News and World Report has some detail in English. : it is clear that, in a country where many people already eke out a precarious existence at the best of times, their loss of their meager income quickly brings on actual hunger. 

(3) I thought of a suitable quote for US Memorial Day. Then I figured I could add nothing to the words of Robert A. Heinlein in The Pragmatics Of Patriotism — his 1973 Forrestal Lecture at the US Naval Academy, Annapolis (of which he himself was an alumnus — he started writing after being invalided out of the US Navy). The full text is available online here. I cannot help being moved everytime I read it, especially the peroration:

The time has come for me to stop. I said that ‘Patriotism’ is a way of saying ‘Women and children first.’ And that no one can force a man to feel this way. Instead he must embrace it freely. I want to tell about one such man. He wore no uniform and no one knows his name, or where he came from; all we know is what he did.

In my home town sixty years ago when I was a child, my mother and father used to take me and my brothers and sisters out to Swope Park on Sunday afternoons. It was a wonderful place for kids, with picnic grounds and lakes and a zoo. But a railroad line cut straight through it.

One Sunday afternoon a young married couple were crossing these tracks. She apparently did not watch her step, for she managed to catch her foot in the frog of a switch to a siding and could not pull it free. Her husband stopped to help her. But try as they might they could not get her foot loose. While they were working at it, a tramp showed up, walking the ties. He joined the husband in trying to pull the young woman’s foot loose. No luck.

Out of sight around the curve a train whistled. Perhaps there would have been time to run and flag it down, perhaps not. In any case both men went right ahead trying to pull her free… and the train hit them. The wife was killed, the husband was mortally injured and died later, the tramp was killed – and testimony showed that neither man made the slightest effort to save himself. The husband’s behavior was heroic… but what we expect of a husband toward his wife: his right, and his proud privilege, to die for his woman. But what of this nameless stranger? Up to the very last second he could have jumped clear. He did not. He was still trying to save this woman he had never seen before in his life, right up to the very instant the train killed him. And that’s all we’ll ever know about him.

THIS is how a man dies. This is how a man lives!

‘They shall not grow old as we that are left grow old;
age shall not wither them nor the years condemn;
At the going down of the sun and in the morning, we shall remember them”

– Tomb of the Scottish Unknown Soldier, Edinburgh

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:

• Switzerland
• Austria
• Denmark
• Israel
• Italy
• Spain
• Germany
• Norway (no active case data maintained, but new cases are dwindling)

 

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.”

https://www.youtube.com/watch?v=JVg8opQkQXc

(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:

https://www.youtube.com/watch?v=KsmmCjxQz6w

(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.

https://www.youtube.com/watch?v=uk2YZfnsOPg

 

COVID19 update, May 20, 2020: reinfection unlikely; correlation between HbA1C and vulnerability to severe disease; German RKI recommendations on masks

Just a quick update today, as workday has been pretty intense.

(1) Dr. John Campbell’s vlog has a special edition on a new report from the South Korean CDC. There have been a number of worrying reports that people tested positive again after recovering, fueling speculation that this could become a chronic disease, like HIV or Hepatitis B. (As he explains, these viruses slip into the cell nucleus and insinuate themselves into the human genome.[*]) Worse, that people could be infectious for life.

However, as it turns out, the tests were false positives. The RT-PCR test detects the presence of a short fragment of RNA that’s specific to the virus, but cannot tell whether this is a remnant of long-destroyed virus, or belongs to a viable virus particle. So when cured patients cough up worn-out lung cells in their sputum, such remnants will trigger a false positive test. This appears to have been the case here.

https://www.youtube.com/watch?v=uATMbGK__Tg

Just as I was typing today’s update, Dr. Seheult posted a video on the exact same study. He has the link to the English version of the Korean CDC report in the description. (Dr. Campbell had to go off second-hand reports, as only the Korean-language version had been released at the time.) Dr. Seheult’s video adds much more detail.

https://www.youtube.com/watch?v=01Rftnxbi6w

I believe this is the great COVID19 news of the day.

(2) Yesterday, the good doctor posted another video with a couple of different segments. One is about a recently published evaluation of four new antibody tests using arrays of known positive and negative samples. http://doi.org/10.1016/j.jcv.2020.104394 “Comparison of Four New Commercial Serologic Assays for Determination of SARS-CoV-2 IgG”

The second is about a paper in the Journal of Diabetes Research, showing a clear link between high levels of glycosylated hemoglobin (high HbA1C values) and severe COVID19. http://doi.org/10.1016/j.diabres.2020.108214 “Glycosylated Hemoglobin Is Associated With Systemic Inflammation, Hypercoagulability, and Prognosis of COVID-19 Patients”

https://www.youtube.com/watch?v=UANgon3Umns

Those of you who are struggling with diabetes (or are trying to avoid going there, as I am) will recognize HbA1C — while blood glucose gives an immediate picture, HbA1C gives an “integral”, as it were, of your blood sugar picture over the last few months, and is less prone to fluctuation due to exertion or recent food or drink intake. [**]

(3) Recently, the topic of face masks has generated extreme passions on both sides, at least in the US. (In Israel, the mask mandate came about as a compromise between the Ministry of Economics, which pushed for accelerated reopening of stores, and the Ministry of Health which wasn’t keen on that. The latter acquiesced in exchange for getting its way on masks. As far as I can tell in my Tel-Aviv borough, the mandate is not being enforced visibly, and indeed in some places is honored more in the breach than the observance.)
Now I would like to think that both sides in the US debate would agree that Germany doesn’t mess around in such matters. (Besides, its statistics in the epidemic speak for themselves.) So what does the Robert Koch Institute (RKI) — their infectious diseases authority — have to say on the matter? Here is their position paper on the subject, which may surprise both the “no masks!” and “must wear masks, because science!” sides. Summarizing in translation:

• most important are good hand hygiene, sneeze-cough hygiene, and maintaining an effective distance of 1.5m (5ft)
• high-grade multilayer masks are foreseen for healthcare workers
• we recommend keeping a simple textile mask handy to wear in specific situation in public, namely where no 1.5m distance can be maintained (e.g., on public transit). [***]
• that said, some people are unable to wear masks at all due to health conditions
• links to “proper wear and care” recommendations for different mask types
• notably absent: any recommendation, let alone requirement, that people need to wear masks in public at all times

[*] What Dr. Campbell skips over is that the RNA is first copied to a double strand of DNA using an enzyme called reverse transcriptase — yes, the RT of RT-PCR testing.

[**] Our red blood cells don’t last much longer getting pumped around our bodies, and hence are continuously replaced by newly manufactured ones, with an average turnover of about 4 months.

[***] I feel compelled to belabor the point that momentary passing-by at closer distance does not mean you are suddenly at risk of infection. Our own Ministry of Health, which recommends 2m (6ft6), only counts exposure as ‘closer than the safe distance for 15 minutes or longer.

COVID19 update, May 13, 2020: more on Vitamin D and on N-acetylcysteine (NAC); Kawasaki disease; “corona poverty” in Belgium

(1) John Campbell has been tirelessly plugging Vitamin D supplementation on his YouTube channel, particularly if you have dark skin and live at Northern latitudes, but even if you have light skin and don’t get outside much. About 40% of the population in Northern Europe and the USA is vitamin D deficient.

Now JoAnn E. Manson, MD, DrPH, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, (Harvard Medical School and Brigham&Women’s Hospital) throws her weight behind it on MedScape. (Video is free, transcript requires free registration.)

[Transcript of video with links.].

I’d like to talk with you about vitamin D and COVID-19. Is there potentially a protective role?

We’ve known for a long time that it’s important to avoid vitamin D deficiency for bone health, cardiometabolic health, and other purposes. But it may be even more important now than ever. There’s emerging and growing evidence that vitamin D status may be relevant to the risk of developing COVID-19 infection and to the severity of the disease.

Vitamin D is important to innate immunity and boosts immune function against viral diseases. We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated.

There are laboratory (cell-culture) studies of respiratory cells that document some of these effects of vitamin D. There’s also evidence that patients with respiratory infections tend to have lower blood levels of 25-hydroxy-vitamin D.

There’s now some evidence from COVID-19 patients as well. In an observational study from three South Asian hospitals, the prevalence of vitamin D deficiency was much higher among those with severe COVID illness compared with those with mild illness. In fact, there was about an eightfold higher risk of having severe illness among those who entered with vitamin D deficiency compared with those who had sufficient vitamin D levels.

There’s also evidence from a meta-analysis of randomized clinical trials of vitamin D supplementation looking at acute respiratory tract infections (upper and lower). This was published in the British Medical Journal 2 years ago, showing that vitamin D supplementation was associated with a significant reduction in these respiratory tract infections. Overall, it was only a 12% reduction, but among the participants who had profound vitamin D deficiency at baseline (such as a blood level of 25-hydroxy-vitamin D of less than 10 ng/mL), there was a 70% lower risk of respiratory infection with vitamin D supplementation.

So the evidence is becoming quite compelling. It’s important that we encourage our patients to be outdoors and physically active, while maintaining social distancing. This will lead to increased synthesis of vitamin D in the skin, just from the incidental sun exposure.

Diet is also important. Everyone should be reading food labels which list the vitamin D content. Food sources that are higher in vitamin D include fortified dairy products, fortified cereals, fatty fish, and sun-dried mushrooms.

For patients who are unable to be outdoors and also have low dietary intake of vitamin D, it’s quite reasonable to consider a vitamin D supplement. The recommended dietary allowance of vitamin D is 600-800 IU/daily, but during this period, a multivitamin or supplement containing 1000-2000 IU/daily of vitamin D would be reasonable.

(2) Kawasaki Disease. This is a rare inflammatory disease in children, of uncertain origin — though an autoimmune origin is suspected by some. Now it has been spotted in children who have been exposed to COVID19 infections — in the US, in the UK, France, and now in Belgium.

There is no proof of a COVID19 link (rather than accidental simultaneous infection), and correlation is not causation, but it’s a rather interesting coincidence that this suddenly pops up — considering all the immune shenanigans of the virus. Here is Dr. Seheult on Kawasaki “systemic vasculitis in childhood”: https://www.youtube.com/watch?v=Ja-jhcXMGj0

(3) I had promised some further remarks about N-acetylcysteine (probably better known to Americans as “NAC”). 

red=oxygen, black=carbon, blue=nitrogen, white=hydrogen, yellow=sulfur

You likely know that amino acids are the building blocks of proteins. These all have the same basic structure: a carboxylic acid (-COOH) group on one end, an amine on the other, and a “side chain” specific to each amino acid (e.g., just hydrogen  of H- for glycine, CH3- for alanine, HO-CH2- for serine,…)

Two amino acids have sulfur in the side chain, namely, methionine (CH3-S-CH2-) and cysteine (HS-CH2-). The HS- group is what chemists call a thiol or mercaptan. (Have you wondered why rotting eggs smell the way they do? Right, decomposition of cysteine gives rise to H2S, HS-CH3, and other smelly stuff that our noses are extremely sensitive to. Likewise with the gaseous, er, digestive byproduct of eating foods rich in cysteine.)

But what is the function of the cysteine side chain really? In a word, disulfide bonds — the “rebar” of biochemistry. If you want to tie adjacent strands of protein together (e.g., strands of keratin in hair), the -SH….HS- pairs in adjacent strands can be oxidized (in the chemical sense) and tied together into a disulfide bond like this: -S—S-

This sort of thing often happens in your lungs when you have a chest cold or a flu, and thus you get a mucous mass that you struggle a bit to cough up.

Enter N-acetylcysteine (NAC), where you have a CH3-C(=O)- group stuck on the nitrogen of the amino acid. What this will do is act as an antioxidant — it will use up the oxidant before it can weld the rebar together.Hence NAC has been in use for a long time as a mucolytic, a.k.a. expectorant (“sputum loosener”) in people with acute or chronic respiratory infections.  (I have used it plenty during chest colds or mild bouts of flu [frequent air travel tends to lead to these ;)]: here in Israel, it’s sold over the counter at pharmacies as effervescent tablets, 200mg of active ingredient per tablet, recommended dose 1 tablet 3x a day dissolved in a glass of water. In the USA, “NAC” can be found in food supplement sections of drugstores etc.)

Turns out, however, that in COVID19 it has other beneficial effects (see yesterday’s bonus video from Dr. Seheult). Especially after being converted in the body to the antioxidant glutathione [*], it will reduce oxidative stress in severe inflammatory reactions. But in addition, it will prevent formation of “rebar” between individual units of von Willebrand Factor (vWF). If such rebar does form, you get long chains of vWF polymer, to which platelets can bind, and you have the beginning of a blood clot. (See also http://biorxiv.org/lookup/doi/10.1101/2020.03.08.982447  for more on disulfide bonds and vWF.)

Unlike more aggressive blood thinners like heparin and warfarin, however, NAC does not significantly increase the risk of hemorrhage. (In stroke patients, overdoing warfarin or low-MW heparins such as https://en.wikipedia.org/wiki/Enoxaparin_sodium runs the risk of exchanging risk of renewed stroke for risk of cerebral hemorrhage — exactly thus Prime Minister Ariel Sharon z”l ended up in a permanent vegetative state. 

(4) Miscellaneous: 

• The economic ravages of long lockdowns, for those not lucky enough to be able to work from home or draw guaranteed salaries. are not limited to the USA anymore — even in a “nanny state par excellence” like Belgium it’s becoming an issue.  De Standaard has an article (in Dutch) about “Corona poverty” in the Flemish cities of Antwerp and Ghent.
• What about COVID19 poverty and Israel? And how much of it because of lockdowns? The tourism industry has been devastated, but that would have happened with or w/o lockdown. A small minority of “gig economy” workers actually saw increased income (delivery drivers for restaurants, in particular) but many small and medium business owners (and their employees) absorbed blows. However, our lockdown was given a “horizon” up front (end of Passover), and we are now largely unlocked except for cafés and restaurants (takeaway and delivery only for now). I will be curious to see our unemployment figures — which have shot up drastically — shake out over the next month or two as furloughed employees return to the workplace.
  Quite a few salaried employees here used up their annual vacation days to wholly or partially bridge the lockdown period.
• “Gender gap”: indications that men have more ACE2 receptors (the virus’s “point of entry”) than women, making them more vulnerable to infection? https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa414/5834646 (via the NYPost, via Sarah Hoyt)
• Could this new Israeli drug, MesenCure, prevent lung damage in COVID19?
• Pfizer wants to expand its human trial for a COVID19 vaccine (developed in collaboration with German drugmaker BioNTech) and is making what in a PR release it has called “risk investments” aiming for an October mass production timeframe.
• The Times of Israel on how also in Israel, doctors treating severe COVID19 patients have moved away from invasive ventilation in favor of noninvasive options—even as they are divided on the reasons why.

[*] For that reason, It is also used intravenously as an antidote in acetaminophen/paracetamol/Tylenol overdose

COVID19, Lag Ba-Omer edition: active cases graphs around (mostly) Europe; more sophisticated model predicts much smaller herd immunity thresholds; Swedish healthcare problems; N-acetylcysteine

Today is the minor Jewish holiday of Lag ba-Omer (33rd day of the omer count), which marks the end of a plague raging in the Holy Land (in the 2nd Century CE) that swept away the disciples of Rabbi Akiva.

(1) Speaking of modern plagues ending, where do we stand in various countries vis-a-vis active cases? Let me show you some graphs (screenshotted from worldometers) below. (Definition, for the avoidance of doubt: active cases = total – cured – deceased.)

below half of peak

one-quarter of peak

1/8 of peak

also about 1/8 of peak

Italy seems to be getting out of the woods now

with fits and starts, but overall trending down

Turning to Scandinavia: Denmark at about half of peak

Recoveries/cured data lack for Norway, but new cases are guttering out. In good shape.

Finland seems to report recoveries on certain days of the week, hence a sawtooth pattern

Sweden is quite another matter (see below)

France has had near-constant active cases for almost a month

Belgium seems to have reached a plateau

Down Under, Australia is doing great, as is New Zealand. But will be watching their numbers as the weather turns cooler there, for evidence of seasonality

The UK is not out of the woods yet. The US is just too big to look upon as a single country — and I cannot easily find recovery data at the individual states’ level. Suffice to say NYC and suburban counties in NJ and CT are skewing the results to such an extent that they mask recoveries in other states.

One remark about the European and Israel graphs with lots of recoveries, however. While these countries all went on lockdown, essentially all of them have “opened up” to greater (Austria) or lesser (Germany) extent — and the “second wave” that people kept talking about has yet to materialize.

(2) Today an interesting preprint crossed my virtual desk.
http://arxiv.org/abs/2005.04704 The authors, from Brown U, Georgia Tech, and the Technical U. of Denmark, look (mostly with paper and pencil math) at models for the spread of an epidemic absent any social distancing, and why these models almost invariably highball estimates of final spread.
TL;DR: they show that if the remaining population’s susceptibility to an infection is not assumed to be “all or nothing” but to span a range, then the first-order behavior of the simple model changes to second-order, and you end up with way lower final states. As a sanity test, they ran the 2009 H1N1 flu (where no social distancing measures were taken) and with their 2nd order model got final numbers of infected way closer to actual serological data than the traditional 1st order model (see figure below).

Related (h/t: masgramondou): https://judithcurry.com/2020/05/10/why-herd-immunity-to-covid-19-is-reached-much-earlier-than-thought/ which points to https://www.medrxiv.org/content/10.1101/2020.04.27.20081893v1

Both papers indicate, among other things, that the infection rate required to reach herd immunity is much lower than the simple first-order model indicates — and the figures would be lower still with some limited social distancing in effect. (Even Sweden imposed some.)

(3) Concerning Sweden, Die Welt (in German) looks at what it calls the Swedish Sonderweg (“special road [taken or followed]”). Notably, it does not attribute the much higher mortality (compared to fellow Scandinavian countries) just to its not entering a lockdown (some voluntary social distancing measures are in place) — but to the “limping” Swedish healthcare system (marodes Gesundheitssystem).
They are at pains to point out that this is not a matter of money — Sweden has the 2nd highest pro capita spending in the EU, after Germany — but of inefficiency, administrative bloat, and wastage. Once upon a time, Sweden had 49.5 ICU beds per 100,000 inhabitants, which today would be the highest in the world, above even the USA. Today? Just 5.8.
Even before the COVID19 crisis, 12% of elective surgery patients has to wait 4 months or more, compared to 2% in France and none at all in Germany. One-fifth of Swedes have to wait more than 2 months for a specialist appointment, compared to only 3% in Germany.
Much like Israel’s public system, rapid access for life-threatening emergencies in Sweden is maintained at the expense of ever greater delays for everything else. [But much unlike Israel, Sweden entered the present crisis without the benefit of a young population and a warm, sunny winter and spring climate…] Doctors in the public system are salaried employees of the state, with all that entails in terms of (lack of) incentives…

(4) Finally, as a “lagniappe” 🙂 a video by Roger Seheult MD about the over-the-counter mucolytic N-acetylcysteine, and how it could be surprisingly useful for COVID19 patients as an antioxidant and even anticoagulant. I will comment on this more tomorrow — gotta run now! Let me add, however, that this one is definitely in the “even if it doesn’t help, it won’t harm” category, as N-acetylcysteine has no meaningful toxicity.

A couple of papers cited by Dr. Seheult:

https://erj.ersjournals.com/content/10/7/1535.short

Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment; S De Flora, C Grassi, L Carati; European Respiratory Journal 1997 10: 1535-1541; DOI:

https://doi.org/10.1016/j.bcp.2009.08.025

N-acetyl-l-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus

https://www.ahajournals.org/doi/abs/10.1161/circulationaha.117.027290

Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi

See also https://en.wikipedia.org/wiki/Von_Willebrand_factor

COVID19 update, May 9, 2020: Spreading reconsidered; German pathologist and Swiss doctors identify thrombosis as #1 killer in severe COVID19, Swiss clinical trial with aggressive anticoagulation treatment; meat supply chain disruptions in Germany

(1) The Daily Telegraph has a long article about an epidemiologist at St Andrews U., Scotland, who has been analyzing a number of epidemiological “contact tracing” studies on how COVID19 spreads.

https://www.telegraph.co.uk/global-health/science-and-disease/coronavirus-spreads-affects-countries-differently/?li_source=LI&li_medium=liftigniter-rhr

https://threadreaderapp.com/thread/1257392347010215947.html

(Quote)

An analysis of such studies was recently posted on Twitter by Dr Muge Cevik, an infectious diseases clinician and researcher from St Andrews University. It was promoted by Sir Jeremy Farrar, the head of the Wellcome Trust and a member of the Scientific Advisory Group for Emergencies (Sage). “If you read one thread,make it this one,” Sir Jeremy said.

(Twitter thread unrolled here)

Dr Cevik starts with a big Chinese study that traced 2,147 close contacts of 157 confirmed Covid-19 cases. The overall infection rate was six per cent, but it was much higher among friends (22 per cent) and family members (18 per cent). In terms of location, the main risk factors were homes (13 per cent) transport (12 per cent) and dinner and entertainment (seven per cent).

Broadly similar findings emerge in several other papers. Risk of infection is much higher within households or other enclosed environments in which contact is close and sustained. In the outdoors, it falls to something in the 0-5 per cent range.

[…]A Chinese study of 392 contacts of 105 confirmed cases found that the attack rate in children was just four per cent within the home, compared with 17.1 per cent in adults, for example. The infection of spouses was super high, at 28 per cent. 

Emphasising the link with age, another study found that household members over 60 were much more likely to become infected (18 per cent) than those under 20 (five per cent).

Children, it seems, are not only better able to resist the infection within the home but also less likely to bring it back with them. A study, funded by the Australian Research Council, of 31 household clusters including children found that only 10 per cent had been sparked by children.

Using these and other studies, Dr Cevik concludes that they suggest (not prove) the following:

[emphases mine in the quote below]

• Close and prolonged contact is required for transmission of the virus. 
• Risk is highest in enclosed environments such as houses, care facilities, public transport, bars and other indoor spaces where people congregate.
• Casual, short interactions are not the main driver of the epidemic. 
• Susceptibility to infection increases with age.

(2) Die Welt has a video interview (in German) with Prof. Nils Kucher at the Zurich university hospital. 

Summarizing his remarks:

• We got severe COVID19 completely wrong in the past. This is changing as overwhelming evidence accumulates, e.g. from autopsies, and is published
• Severe COVID19 is not a conventional viral disease at all, but a coagulation disease
• Endothelial cells have ACE2 receptors. The virus docks there, cause inflammation of the endothelium, this leads to release of cytokines. (Cf. “cytokine release syndrome”, a.k.a. “cytokine storm”.) Thrombosis ensues, and eventually the patient dies of embolisms
• It has taken us way too long to figure that out, which has cost needless lives
• The way to prevent thrombosis is treatment with [?]molecular weight heparin. Guidelines traditionally limit this to hospital settings because of the risk of hemorrhage 
• Often patients seem to be in decent shape, are sent to home isolation with just antifebriles, and then some die of thrombotic events
• Now we [=Zurich U. Hospital] are running a clinical trial on 1,000 ambulatory COVID19 patients. Half get standard care, the other half also get heparin injections. All are closely monitored by telephone in case something goes awry. For the heparin treatment with that patient group, the risk of hemorrhage is rated as less than 1%
• Sadly, doing a control group creates an ethical problem if it’s a deadly disease and you are pretty sure you have the answer

Related: a Hamburg coroner, Dr. Klaus Püschel , talks about what he has learned from 192 autopsies on COVID19 patients (Under a law in the Free City of Hamburg, autopsies are mandatory for deaths from an infectious disease.)

“Of the first dozen I autopsied, seven died of thrombose, four directly of lung embolisms.” 

Those results were just published [following peer review by four experts, which takes a while] in the Annals of Internal Medicine. http://doi.org/10.7326/M20-2003

Independently of his colleague in Zurich, Hamburg University Hospital Prof. Stefan Kluge wonders if treatment of severe COVID19 patients should not primarily feature anticoagulant therapy.

[My “gut” tells me: a combination of anticoagulants and immunomodulators.]

Coroner Klaus Püschel : “This isn’t a killer virus, we’re not at war. We must not fear and should not give up.”

(3) Now even De Standaard (in Dutch) has woken up to the problem of food insecurity in the US. The article is a mixed bag: the journalist is clearly  floored by the generosity of Americans (in “nanny states” like Belgium, there is a tendency on the part of people to say, “oh, helping people, that’s the government’s job”). At the same time gets taken in by socialist snake oil peddled by the likes of “Beta” O’Rourke.

(4) On a related note, supply chain disturbances for meat are not just a US phenomenon: Here are two articles telling of outbreaks at two meat processing plants, one in Schleswig-Holstein in the North, the other in Baden-Württemberg in the South.

Consequently, meat prices are rising in Germany.

COVID19 update, May 7, 2020: risk of severe case presentation increases with age too; meat processing plants; fraying lockdowns; Georgia (the country)

Busy day at work, so just some quick updates:

(1) There is a commonly quoted rule of thumb that 80-85% of COVID19 cases are mild, and the rest severe and life-threatening. But how constant is that ratio really?

I was emailed a copy of a report (in Hebrew) by a group that was consulted for our national COVID19 planning. In the section on expected hospital load was a table with a breakdown of hospital and ICU admissions by age bracket, apparently taken from a CDC Morbidity and Mortality Weekly Report, http://dx.doi.org/10.15585/mmwr.mm6912e2. Screenshotting the table here:

* Lower bound of range = number of persons hospitalized, admitted to ICU, or who died among total in age group; upper bound of range = number of persons hospitalized, admitted to ICU, or who died among total in age group with known hospitalization status, ICU admission status, or death.

Needless to say, these are data early in the epidemic (when the group had to make its recommendations). But if we use ICU admissions as a proxy for the number of severe cases, then we see a clear increase with age, the way it is seen for mortality.

(2) Elsewhere on the CDC site, one finds a report about the conditions and challenges at meat processing plants https://dx.doi.org/10.15585/mmwr.mm6918e3
Some quotes:

During April 9–27, aggregate data on COVID-19 cases among 115 meat or poultry processing facilities in 19 states were reported to CDC. Among these facilities, COVID-19 was diagnosed in 4,913 (approximately 3%) workers, and 20 COVID-19–related deaths were reported. Facility barriers to effective prevention and control of COVID-19 included difficulty distancing workers at least 6 feet (2 meters) from one another (2) and in implementing COVID-19-specific disinfection guidelines.* Among workers, socioeconomic challenges might contribute to working while feeling ill, particularly if there are management practices such as bonuses that incentivize attendance. 

 Facility challenges included structural and operational practices that made it difficult to maintain a 6-foot (2-meter) distance while working, especially on production lines, and in nonproduction settings during breaks and while entering and exiting facilities. The pace and physical demands of processing work made adherence to face covering recommendations difficult, with some workers observed covering only their mouths and frequently readjusting their face coverings while working. Some sites were also observed to have difficulty adhering to the heightened cleaning and disinfection guidance recommended for all worksites to reduce SARS-CoV-2 transmission.

Solutions to structural and operational challenges that some facilities adopted included adjusting start and stop times of shifts and breaks to increase physical distance between workers. Outdoor break areas were added at some facilities to decrease contact between workers. Some facilities installed physical (e.g., plexiglass) barriers between workers; however, this was not practical for all worker functions. Symptom and temperature screening of workers was newly instituted in some facilities and improved in others.

Sociocultural and economic challenges to COVID-19 prevention in meat and poultry processing facilities (Table 2) include accommodating the needs of workers from diverse backgrounds who speak different primary languages; one facility reported a workforce with 40 primary languages. This necessitates innovative approaches to educating and training employees and supervisors on safety and health information. In addition, some employees were incentivized to work while ill as a result of medical leave and disability policies and attendance bonuses that could encourage working while experiencing symptoms. Finally, many workers live in crowded, multigenerational settings and sometimes share transportation to and from work, contributing to increased risk for transmission of COVID-19 outside the facility itself. Changing transportation to and from the facilities to increase the number of vehicles and reduce the number of passengers per vehicle helped maintain physical distancing in some facilities.

(3) Lockdowns — useful as they undeniably are in densely populated urban regions — are not something that can be maintained forever. In the “hammer and dance” strategy of Tomas Pueyo, the “hammer” — the lockdown to break the epidemic’s back — is supposed to be hard and short, followed by a maintenance phase — the “dance” — that favors such social distance measures as yield the maximum reduction for minimal economic cost. (Face masks are one example.)
There are increasing signs that lockdowns in the US are fraying. Bethany Mandel, who lives in New York, speaks for many who express a sense that politicians of a certain stripe now keep “moving the goalposts” way beyond the original justification for lockdowns, and that they are completely oblivious to the staggering and still mounting economic costs for those who do not have guaranteed government paychecks. “We are tired of being treated like children,” one reads numerous times in the comments.[*]

Days ago, a hairdresser in Texas who had reopened her business made a tearful plea that she not be punished for wanting to feed her children. She was convicted to seven days in prison and a $7K fine. Now in a dramatic turn of events, not only have both the state Attorney-General and the Governor criticized the “excessive” punishment (the lockdown over hardressing salons ends Friday anyhow), but the state’s Lt.-Gov. donated the money from his own pocket and offered to serve the 7-day sentence himself as a proxy for the woman.

(4) DIE WELT looks at what it calls the “Coronavirus Model Pupil,” Georgia (the country, not the US state). The country, knowing it could ill afford such a calamity, locked down proactively rather than reactively, and is now exiting. (Possibly the most prescient thing it did was cut air links to China before they even saw their first case.) Now, despite a social culture much like Italy, it got a sum total of 610 cases, with just 9 (nine) dead.

(5) Finally, hard-hit Belgium is reopening after a few false starts. Summarizing the report from De Standaard (in Dutch):

• starting May 10, every household can receive and host four designated people (a fixed list of four). Recommended to sit outdoors. No travel distance limitation

• May 11, shops will open. One customer per 10m^2 (110 sq.ft.) floor area. Wearing a mask is recommended but not mandatory; generally recommended in situations where 1.5m (5ft) distance cannot be maintained (e.g. on public transit). If lines develop, elderly, handicapped, and care workers get priority

• public transit in principle reserved for people who have no private means of transportation (cars, motorcycles). In practice, this will not be enforced

• restaurants, cafés, cultural centers remain closed for now

• public sports events are put off until July 31

[*] Without engaging in partisan political rhetoric: one reason the lockdown in Israel was largely successful, and saw a compliance well above what one might expect of our garrulous nation, was that we were treated like adults. Economic trade-offs were honestly discussed, including the limits to how long we could lock down before irreparable damage to our economy would ensue — and we were given a realistic time horizon from the start. At no point was there a sense of “bait and switch”.

UPDATE: via the Jerusalem Post, this interesting paper in the Journal of Medical Virology has an interesting theory about why the SARS-nCoV-2 coronavirus may elicit potentially fatal “cytokine storm” so much more often than seasonal influenzaviruses: https://doi.org/10.1002/jmv.25866

We have applied mathematical modeling to investigate the infections of the ongoing COVID‐19 pandemic caused by SARS‐CoV‐2 virus. We first validated our model using the well‐studied influenza viruses and then compared the pathogenesis processes between the two viruses. The interaction between host innate and adaptive immune responses was found to be a potential cause for the higher severity and mortality in COVID‐19 patients. Specifically the timing mismatch between the two immune responses has a major impact on the disease progression. The adaptive immune response of the COVID‐19 patients are more likely to come before the peak of viral load, while the opposite is true for influenza patients. This difference in timing causes delayed depletion of vulnerable epithelial cells in the lungs in COVID‐19 patients while enhancing the viral clearance in influenza patients. Stronger adaptive immunity in COVID‐19 patients can potentially lead to longer recovery time and more severe secondary complications. Based on our analysis, delaying the onset of adaptive immune responses during early phase of infections may be a potential treatment option for high risk COVID‐19 patients. Suppressing the adaptive immune response temporarily and avoiding its interference with the innate immune response may allow the innate immunity to more efficiently clear the virus.

COVID19 update, May 4, 2020: French evidence that epidemic got to Europe in December; intriguing hydroxychloroquine find; Michael Levitt interview

(1) Via reader Yves [not Cohen], a French media report that COVID19 was found in a blood sample taken from a lung patient at a suburban Paris hospital on December 27, 2019. [Hand-corrected DeepL translation]

Invited on the set of BFMTV on Sunday, May 3, Professor Yves Cohen, head of the intensive care unit at the Avicenne hospital in Bobigny (Seine-Saint-Denis), and at the Jean-Verdier hospital in Bondy (Seine-Saint-Denis), claims to have had a patient infected with Covid-19 at the end of December 2019. […] “We had a positive case at Covid-19 on 27 December 2019, when he was hospitalised with us at Jean Verdier,” he explained on the air. An analysis of the serological PCR tests carried out on the 24 pneumonia patients in December and January in these two hospitals led to this conclusion.[…] Dr Olivier Bouchaud, an infectiologist at the same Avicenne hospital, confirms this information. “PCR samples taken from a patient clearly show that he [tested positive for] Covid. We did have a first case in France on 27 December,” he adds. […] Professor Cohen mentioned that the infected patient had been ill for 15 days and that he had infected his two children, but not his wife. This person had not made any recent trips. For Doctor Bouchaud, “this does not necessarily mean that he is patient zero in France. But it does suggest that more research is needed to find out”. […] So far, the first officially recorded cases in France are those of three people, on January 24: a Frenchman of Chinese origin and two Chinese tourists who stayed in Wuhan, the original focus of the epidemic which appeared in December.

This, together with the earlier report that COVID19 was found during autopsy of a Santa Clara County patient who had died early February (which places the infection roughly at mid January), pushes the COVID19 timeline further back. [The French story is of course being picked up in Chinese propaganda media as “proof” that the virus did not come from China. Mais bien sûr, et je m’appelle Napoléon Bonaparte.]

(2) In the middle of an article about an Italian pharmacist who claims she has uncovered the main mechanism behind severe COVID19 this interesting nugget can be found:
“Chiusolo told the Post, the Italian Society of Rheumatology interviewed 1,200 rheumatologists throughout Italy to collect statistics on contagions. Out of an audience of 65,000 chronic lupus and rheumatoid arthritis patients who systematically take hydroxychloroquine, only 20 patients tested positive for the virus [and none of those ended up in the ICU or died].”
Time for a little back-of-envelope calculation. According to Worldometers, Italy has 210,717 documented cases out of a population of 60.2 million, or 0.35% of the population. This is almost certainly a gross underestimate, but 0.35% of 65,000 lupus and rheumatoid arthritis patients would be 228 — more than ten times the observed number.

An interesting control would be to check patients on some other long-term mild immunosuppressor drug (steroids? Multiple Sclerosis patients on Copaxone? Reader Laura R. suggests https://en.wikipedia.org/wiki/Methotrexate )

(3)

Mike Levitt, 2013 Nobel Prize winner in Chemistry, getting interviewed about COVID19 on UnHerd. I disagree about 30% of the time (and he should hire a fact-checker — his claim that Germany did not go on lockdown is peculiar to say the least), but a lot to chew on. 

He has a rather interesting way of expressing mortality: weeks-equivalent of annual all-causes mortality. He estimates COVID19 will end up being about 4 weeks worth, which may be an easier number to grasp and keep in their head for people who don’t juggle data all day in their day jobs.

(4) Via Instapundit: a long WIRED article “inside the early days of China’s coronavirus cover-up”. https://www.wired.com/story/inside-the-early-days-of-chinas-coronavirus-coverup/

Seasoned journalists in China often say “Cover China as if you were covering Snapchat”—in other words, screenshot everything, under the assumption that any given story could be deleted soon. For the past two and half months, I’ve been trying to screenshot every news article, social media post, and blog post that seems relevant to the coronavirus. In total, I’ve collected nearly 100 censored online posts: 40 published by major news organizations, and close to 60 by ordinary social media users like Yue. In total, the number of Weibo posts censored and WeChat accounts suspended would be virtually uncountable. (Despite numerous attempts, Weibo and WeChat could not be reached for comment.)

Some people say this is China’s Chernobyl. On the contrary. While both disasters happened under totalitarian Communist regimes, COVID19 makes Chernobyl look like a kitchen ketchup spill. 

(5) Bloomberg looks at how the Hawaii tourist industry (about 20% of the island’s economy[*]) has been devastated by the pandemic. At least they have the naval and other military presence to keep the rest of their economy going, plus some agriculture.

[*] indirectly it’s more, of course. In another illustration of Bastiat’s timeless essay “That which is seen and that which is not seen” (original title: Ce qu’on voit et ce qu’on ne voit pas), the sudden drop in purchasing power of those working in the tourist industry has a knock-on effect in other sectors.

UPDATE: what does the milder version of the disease feel like? In this article from March 12, a woman age 37 from the Seattle area shares her experiences:

Schneider revealed how she first began experiencing flu-like symptoms on Feb. 25. The symptoms occurred three days after she attended a party that was later identified as the place where at least five others caught the bug.

“I woke up and I was feeling tired, but it was nothing more than what you normally feel when you have to get up and go to work, and I had been very busy the previous weekend,” she said.

She felt a headache coming on around noon, along with fever and body aches. This was enough to cause her to leave her office at her biotechnology firm and head home.

The marketing manager napped but woke with a temperature that peaked at 103 degrees Fahrenheit that night.

“And, at that point, I started to shiver uncontrollably, and I was getting the chills and getting tingling in my extremities, so that was a little concerning,” she said.

She took over-the-counter flu medication, and called a friend to be on standby in case she needed to be taken to the hospital, but the fever receded over the following days.

Schneider wrongly assumed she didn’t have COVID-19 because she didn’t experience the usual symptoms such as coughing or shortness of breath.

She was up to date with her flu shot, but thought her illness was due to a different strain. When she visited her doctor, she was instructed to go home, rest up and drink large amounts of fluids.

The way she began to suspect she had something more serious was via social media. A friend on Facebook posted that several folks from the party had developed similar symptoms. These people went to their doctors, where they tested negative for the flu, but were not offered coronavirus tests because they were not showing the common signs of coughing and difficulty breathing.

Smartly, Schneider enrolled in a research program called the Seattle Flu Study in hopes of getting to the bottom of her sickness. She was mailed a nasal swab kit by the researchers, which she mailed back. Then began a wait of several days.

On March 7, she got a call with the bad news: She had tested positive for COVID-19. Surprisingly, Schneider felt relieved. “I was a little bit pleasantly surprised, because I thought it was a little bit cool,” she told the AFP, adding that she found it interesting from a “scientific perspective.”

Her symptoms had already subsided by the time she was diagnosed.

COVID19 update, May 3, 2020: Medical bureaucrats vs. frontline medicine; Israel vs. Belgium; agriculture turns away from globalized agribusiness and toward local market

(1) John Hinderaker of Powerline contrasts the hidebound “academic medicine types” who dominate the medical agencies and healthcare bureaucracies with the more daring doctors on the frontlines of the epidemic. 

He specifically refers to a story I have been covering here at some length: the changing understanding of the severe COVID19 disease picture as primarily “immune systems killing the patients in order to have them”. (The milder disease picture without lower lung involvement — which accounts for the overwhelming majority fo COVID19 cases — is typically a self-limiting ailment ranging from a mild cold to a nasty bout of flu.)

A group of critical care physicians representing the University of Tennessee, the University of Wisconsin, Eastern Virginia Medical School, the University of Texas and a number of other institutions have formed the Front Line COVID-19 Critical Care Consortium and released a bulletin setting out a recommended treatment protocol. The protocol is based largely on the fact that it is not the virus, but the body’s reaction to the virus, that kills patients:

[I]t is the severe inflammation sparked by the Coronavirus, not the virus itself, that kills patients. Inflammation causes a new variety of Acute Respiratory Distress Syndrome (ARDS), which damages the lungs.

Practicing doctors are highly familiar with inflammatory conditions and a number of known treatments have been adapted to COVID-19. The linked bulletin advocates early intervention–the key–using Vitamin C, heparin, Methylprednisolone and Hydroxychloroquine.

Dr. Paul Marik, Chief of Pulmonary and Critical Care Medicine at the Eastern Virginia Medical School, published a Critical Care COVID Management Protocol along similar lines. As a preventive measure, Dr. Marik recommends a combination of Vitamin C, Vitamin D, zinc and melatonin. Dr. Malik notes that “[w]hile there is no high level evidence that this cocktail is effective; it is cheap, safe and widely available.” For what it is worth, I have been following this regimen for some time.

Interestingly, in my own field of science (as in many others), it is precisely the academics who push for innovation, and the industrial users of the science and tech who are hidebound. However, frontline medicine is a different matter than, say, analytical chemistry: if you have patients dying on you — and what “the book” tells you isn’t working — you start trying to think outside the book. The much-maligned steroids actually do a lot of good in acute autoimmune or allergy attacks (I’ve gotten them following a suspected allergic reaction to an antibiotic). Sure, you don’t necessarily want to rely on steroids for long-term case management if you can help it, — but here you’re trying to stop a patient from getting killed by a massive immune over-response.

(2) The director-general of Israel’s health ministry positively evaluates the outcome of Israel’s containment/mitigation strategy: we actually have one of the lowest case fatality rates in the developed world. “If we hadn’t been tough, we’d have been in the same boat as Belgium”, he said. Belgium has a slightly larger population than Israel, and so far has 7,844 dead, compared to just 230 in Israel.

To be fair, of course, Israel has several factors on its side that Belgium didn’t:

• a much sunnier and warmer climate — this both reduces the ability of the virus to spread (as the DHS study showed, virus deposits on surfaces are neutralized by bright sunlight)   *and* the additional vitamin D boosts the immune system of humans

• Israel has a much younger population pyramid than Belgium (or Germany, or…) — which in and of itself will reduce mortality (in Germany, just one percent of dead are below age 50).
• Israeli can seal its borders with comparative ease
• War and terrorism being a permanent risk in Israel, both its medical systems and its population may be more primed to respond to calamities

This is aside from Belgium counting many deaths as “of COVID19” that were really from other causes, “with” actual or suspected COVID19. (Otherwise, it is impossible to explain why its absolute mortality exceeds that of next-door Germany, which has 7x the population.)

(3) Miscellaneous updates:

• De Standaard (in Dutch) looks at the changing agricultural landscape in Belgium and The Netherlands. Farmers are getting second thoughts about big agribusiness on low margins, becoming dependent on export markets halfway around the planet , which demand is now at zero while people in the next town or county want to buy vegetables. “Locavores” (eating local) is an expensive snobbish trend in some parts of the USA, but quite feasible in Northwest Europe. 

• Germany reopens by Länder (“lands” of the federal republic) reports DIE WELT. Saxony-Anhalt, Thuringia, and the Saarland blaze the trail  https://www.welt.de/politik/deutschland/article207678739/Coronavirus-Sachsen-Anhalt-Sachsen-Saarland-Thueringen-lockern-Beschraenkungen.html?fbclid=IwAR0ik0ZgqUc-5ZuDD1r6xhr3aWbevUkRqqKEaAdUAAfdyhytIa21uY7orKY
• I got Emails from a shoe store in The Hague that they are discontinuing free shipping, as stores reopen in The Netherlands tomorrow
• An article looks at how airplane travel may change forever https://www.jpost.com/international/how-will-coronavirus-change-air-travel-forever-626693

COVID19 update, May 2, 2020 edition: Remdesivir gets FDA approval; detailed German statistics

(1) The top news item of the day is probably that Gilead Scientific’s antiviral drug remdesivir was given FDA Emergency Approval for use in COVID19 patients. Remdesivir is not a “magic bullet”, but it’s a start.

(2) Roger Seheult MD, pulmonologist and medical school instructor, gives a 1.5 hour recap video on what we know about COVID19.

(3) Miscellaneous updates:

• the Ma`ayanei haYeshua [Wellsprings of Salvation] hospital in Bnei Brak, Israel (a COVID19 hotspot) has deployed an Israeli-developed UV-C room sterilization system. This is of broader relevance than COVID19, and if successful, will prove very helpful in the protracted and increasingly worrying struggle against hospital “superbugs” — bacteria resistant to every known antibiotic. (Such bacteria tend to develop in hospitals and long-term care settings through “Darwinian selection”, as both infections and treatment with aggressive antibiotics are frequent.)
• Die Welt has a detailed video (in English, with German subtitles) on significant progress with a vaccine in the USA
• worrisome reports about some peculiar COVID19-like pediatric syndrome noted in earlier updates: these now appear to have been identified as Kawasaki’s disease, which is of uncertain origin but some sort of autoimmune etiology is suspected. Coincidence or new cases triggered by COVID19 infection?
• disturbing reports of COVID19 “reinfections” in South Korea appear to have been false positives in the test
• Abbott’s new rapid COVID19 test, which claims 99% accuracy, has been approved for use in Europe.
• if you give people perverse incentives to cook the books, and don’t balance that out with a deterrent for the act of cooking — well, don’t be surprised if books get cooked. NYC funeral director on candid recording about people who obviously died from otehr causes being coded as COVID19. Mind you, I am sure the un-inflated COVID19 mortality in NYC would be quite bad enough (“thanks” to very high pollution density and the subway as “the mother of all superspreaders”) — but those numbers struck me as anomalously high from the start. (As discussed in previous updates, numbers from Italy and Belgium are inflated for different reasons.)

(4) In contrast, countries like South Korea and Germany have rather more scrupulous reporting standards. I’ve linked previously to the daily Korean CDC reports: here is the detailed daily update (in English) from the Robert Koch-Institute (Germany’s infectious diseases authority, named after the discoverer of the tuberculosis pathogen). A few highlights from the daily report:

• Only 19% of all cases occurred in persons aged 70 years or older — but these account for 87% of deaths.
• cases per 100,000 people in age cohorts are fairly homogenous across age cohorts 20-29 through 70-79, climb sharply in the highest age cohorts, and drop steeply for ages 10-19 and especially 0-9.
• mortality in age cohorts 0-9 and 10-19 are ONE (1) patient each, while age cohorts 20-29 and 30-39 account for just 6 and 14 deceased out of a total of 6,472. Yes, Virginia, ages below forty account for just 0.3% of all dead, and all ages below fifty for just 1%. Fifty-somethings add another 3.2%, sixty-somethings another 9.0%.
• Their technique of estimating the effective reproductive number R consists of dividing the 4-day moving average of new cases by the one 4 days earlier. At present it is R=0.79, with a 95% confidence interval of 0.66–0.90. Any R value below 1 implies that the epidemic will wither away, while any value over 1 implies slower or faster exponential growth.
• the report points to a European Union website with all-causes excess mortality graphs. These serve as a useful “sanity check” on COVID19 death reporting criteria for different countries.

COVID19 update, April 28, 2020: drug repurposing; perverse incentives; Neil Ferguson now sees further lockdowns as impractical

(1) “Drug repurposing”: it’s a thing. Basically, if you have an emerging disease and need a remedy right this minute — even if you design a new drug that works well in the test tube, you are still faced with months of Phase 1, 2, and 3 clinical trials.

In contrast, if you can repurpose an existing drug that is already approved for treatment of another condition, you can skip testing whether the drug is safe, what side effects it has, and what is a safe dosage range. (As the old quip goes, nothing is safe at all doses, not even dihydrogen monoxide ;)) All you need to establish is: does it work against the new disease?

So there have been massive efforts to screen databases of approved drugs for molecules that inhibit this, that, or the other enzyme that is a vital part of the viral reproduction cycle. Increasingly, the first step of this is done on the computer, and the most promising candidates are then tested out in vitro, then in “animal models”.

But sometimes scientists stumble serendipitously on something that seems to work. SCIENCE magazine reports on… the H2 antagonist famotidine (sold in the US under the brand name Pepcid), used widely as a heartburn remedy until more recently displaced by proton pump inhibitors such as omeprazole (Prilosec).

“The virus was killing as many as one out of five patients older than 80 [in Wuhan]. Patients of all ages with hypertension and chronic obstructive pulmonary disease were faring poorly. Callahan and his Chinese colleagues got curious about why many of the survivors tended to be poor. “Why are these elderly peasants not dying?” he asks.

In reviewing 6212 COVID-19 patient records, the doctors noticed that many survivors had been suffering from chronic heartburn and were on famotidine rather than more-expensive omeprazole (Prilosec), the medicine of choice both in the United States and among wealthier Chinese. Hospitalized COVID-19 patients on famotidine appeared to be dying at a rate of about 14% compared with 27% for those not on the drug, although the analysis was crude and the result was not statistically significant.

But that was enough for Callahan to pursue the issue back home. […]

“Anecdotal evidence has encouraged the Northwell researchers. After speaking to Tracey, David Tuveson, director of the Cold Spring Harbor Laboratory Cancer Center, recommended famotidine to his 44-year-old sister, an engineer with New York City hospitals. She had tested positive for COVID-19 and developed a fever. Her lips became dark blue from hypoxia. She took her first megadose of oral famotidine on 28 March. The next morning, her fever broke and her oxygen saturation returned to a normal range. Five sick co-workers, including three with confirmed COVID-19, also showed dramatic improvements after taking over-the-counter versions of the drug, according a spreadsheet of case histories Tuveson shared with Science. Many COVID-19 patients recover with simple symptom-relieving medications, but Tuveson credits the heartburn drug. “I would say that was a penicillin effect,” he says.”

“After an email chain about Tuveson’s experience spread widely among doctors, Timothy Wang, head of gastroenterology at Columbia University Medical Center, saw more hints of famotidine’s promise in his own retrospective review of records from 1620 hospitalized COVID-19 patients. Last week, he shared the results with Tracey and Callahan, and he added them as a co-authors on a paper now under review at the Annals of Internal Medicine. All three researchers emphasize, though, that the real test is the trial now underway. “We still don’t know if it will work or not,” Tracey says.”

I am definitely looking forward to the results of that trial.

(2) I have heard the claim made that US hospitals have a financial incentive to code a patient as COVID19. Given the complexity of the US health insurance market (and governmental players in it), it struck me as “plausible, but verify”. Turns out: yes, Virginia. (The article notes that notoriously left-biased Snopes agrees with them.)

In our own system, there is no financial incentive to do so as it all comes out of the same insurance pool (divided among the four authorized HMOs by enrollment, not actual costs). Whatever downsides our socialized-with-private-options medical system may have, a perverse incentive to code a non-COVID19 patient as COVID19 is not one of them. As a result, we have “only” 208 COVID19 deceased at the time of writing, according to the Ministry of Health’s daily update.

A source in Belgium’s medical community told me that pathologists massively write COVID19 as the cause of death “if the patient has even been near a COVID19 case”, even if the actual cause is heart attack, stroke,… This appears to be one reason for the anomalously high per-capita COVID19 mortality in Belgium (the highest in the world, and far in excess of next-door Germany which uses much stricter criteria). When all-cause mortalities were compared year over year, an excess mortality was found that is comparable to neighboring countries.

(3) In this interview with Imperial College modeler Neil Ferguson https://www.youtube.com/watch?v=6cYjjEB3Ev8 (yes, the one with the “two million million will die” model, that later got revised drastically downward) he seems to take a more nuanced position than some of his acolytes, sees continued lockdown as unrealistic “and causing excess mortality from other causes” (!), expects a second wave (he’s not alone in that), and favors a South Korean-style test, track & trace approach. Defends himself as “as a nation, we acted in time to prevent a breakdown of medical services”. For balance, I offer a video on the same channel by his Swedish critic Prof. Johan Giesecke. https://www.youtube.com/watch?v=bfN2JWifLCY The interviewer is fairly tough on both: nice to see some actual journalism.

(4) in John Campbell’s daily update, https://www.youtube.com/watch?v=lu00u2dEnbs about 16 minutes in, John Campbell discussed “pediatric inflammation syndrome” in the UK. Is it COVID19 or some unidentified viral pathogen? Abdominal pain, GI symptoms more annoying than anything else, cardiac involvement more worrisome. “Let’s hope that comes to nothing, but would seem to be expedient to have a higher index of suspicion [of abdominal pain in children].”

He also thinks Canada is starting to look good.

(5) Miscellaneous updates (h/t Mrs. Arbel):

• pathologists are reshaping the time line of when the virus arrived to the USA. https://www.wsj.com/articles/pathologists-hunt-for-earlier-coronavirus-cases-in-new-york-11588003955 For instance, in early February, a 57-year old woman in Santa Clara County, CA (read: Silicon Valley) died of what later found to be COVID-19. [Note that, since it takes 2-3 weeks to get sick enough to die of the virus, that implies she was infected around mid-January.]

• The secretive group of scientists and billionaires pushing for a Manhattan Project against COVID19 (which would not be specific to SARS-nCoV-2 but likely cover the entires family of coronaviruses) https://www.wsj.com/articles/the-secret-group-of-scientists-and-billionaires-pushing-trump-on-a-covid-19-plan-11587998993?mod=trending_now_1
• Israel Aircraft Industries proposes UV-C based “sterilization robot” for passenger airplanes. This technique is both more effective than disinfectant fluids, works faster, and does not require “drying time” after treatment.  https://www.jpost.com/israel-news/israels-iai-tests-uv-light-solution-to-sterilize-passenger-aircraft-625983

Today, Israel marks Yom HaZikaron, or Memorial Day, for its fallen soldiers. Tonight (days on the Jewish calendar run sundown to sundown) it will transition into Yom HaAtzmaut or Independence Day — the former to remind us of those who paid the ultimate price for the latter.

COVID19 update, April 27, 2020: Israel and Europe progress; worrisome signs in the US food supply chain; Bastiat and “non-urgent” healthcare

(1) Let’s have a quick roundup of the latest active cases data from worldometers (I’ll leave Israel to the last):

Germany’s active cases 39,794 are down to 55% of the peak value on April 4, 72,865. Switzerland is doing better still — 5,651 down from a peak of 14349 on March 31, or down to 39% of peak. Austria stands at 2,401, or down to 26% of its April 3 peak of 9,334. Norway’s graph has no info on recoveries (hence no useful info on active cases), but daily new cases are a fraction of their peak. Total dead are clearly nearing the top of the sigmoid at 201. Finland’s graph looks like a wild zigzag owing to intermittent reporting of recoveries — but seems to be trending the right way. Active case graphs in Spain, Italy, and France seem to indicate these countries are turning the corner — if they can prevent a second flare-up.

Belgium, however, is not out of the woods yet, nor are the Netherlands and the UK. Sweden looks murky, with active case numbers still climbing about linearly, but total deaths seemingly starting to level off. The US — overall looks pretty grim still, but if greater New York City were taking out of the equation, the rest of the country looks rather rosier.

As for Israel: our active cases have been dropping steadily since April 15, from a high of 9,808 to the present 8,511. Recoveries have exceeded new cases since April 16. The total number of dead has crossed the 200 mark, but the curve over time shows a clear sigmoid that appears to be close to leveling off. With 15,443 documented infections since the beginning of the crisis (of which 6,731 documented recoveries), our apparent “case fatality rate”, at 201/15,443*100% = 1.3%. However, keep in mind that Israel counts everybody who tests positive, whether they develop symptoms or not. Guesstimating about half of these to be asymptomatic, the true CFR may be closer to double that, while the true IFR (infection fatality rate) is certainly lower than 1.3%, as despite increased testing capability the country is sure to have a significant Dunkelziffer/stealth infection rate. (Do keep in mind Israel has a much younger population pyramid than the major developed countries — this alone accounts for our low number of severe cases. The stories of young and healthy people without pre-existing conditions getting severe COVID19 are “man bites dog” news, not significant shares of the patient population.)

Israel indeed has done something today that I can only hope the US is wise to do soonest: opened its hospitals and HMO policlinics for elective procedures. (A lot of “gray area” care is technically elective in that it doesn’t have to happen right this second — but any unnecessary delay will cause complications later.)

Finally, in India lockdown is to end May 3, but it’s getting rolled back already in some less-stricken locations.

(2) Rather more worrisome news from the US, with twin posts (here and here) reporting about food supply chain disruptions from the agricultural side of things. I reached out to a few people informed about goings-on, and the problems are basically threefold:

• Choke points in the distribution chain were created by COVID19 outbreaks at meat processing plants (like Smithfield’s in South Dakota), which necessitated closure, sanitation, and reopening at reduced capacity. (At some processing plants, workers are also reluctant to show up.) Hence, farmers are stuck with hogs etc. and no place to have them processed.
• Farmers whose chief outlet was to the large food service companies and institutional customers are now stuck with product they cannot unload, except at a loss. Their operational cash headroom is limited at the best of times;
• Meanwhile, those who supply to the grocery chains see shifting demand. Dairy, for instance, is down. This has caused prices paid to farmers to drop to “below cost” levels.

There are second-order effects: corn growers who primarily supply pig farmers etc… And with oil prices down to historical lows, selling corn for ethanol is not practical. (Incidentally, while some farmer supplies (e.g., fuel) are cheaper, others go up in price because imported from, you guessed it…)

I doubt dire predictions of famine in the USA will come to pass (and dearly hope and pray they won’t). However, remember the USA is a major food exporter — and that it is likely to apply the maxim “the poor of my own city come first” in a serious food crisis. So major shortages in countries that are dependent on US food imports are increasingly likely. 

“Just-in-time” supply chains can normally respond smoothly to ordinary shifts in demand, and thus keep prices down for the end consumer. However, they are fragile to major disruptive events like COVID19. The old engineer’s maxim “better, cheaper, faster — pick any two” seems to have a supply chain counterpart: “cheap, just in time, robust: pick any two”. 

The social distancing measures in the USA (outside greater NYC,  and perhaps a few other congested metropolitan areas) have crossed the line from diminishing returns territory into doing more damage than they prevent — it is high time to return no normality. Scott Atlas MD definitely agrees.

(3) On a final note: Dr. Paul Hsieh quotes Bastiat about “the seen vs. the unseen [costs]” in the context of emergency care. (Bastiat’s classic essay expounding the concept of hidden costs and consequences should be required reading, not just for any economics student, but for every public servant and every elected official.) The number of COVID-19 deaths are in the public eye. The number of people dying from cardiac complications or ruptured appendicitis because they were unwilling to come to the ER for fear of contracting COVID19 (a phenomenon seen in Europe as well as the US) are not so obvious — but they are still there. This is without going into the urgency level one step below: cancer surgeries, non-emergency bypass surgeries,…

UPDATE: John Tyson, chairman of the board of Tyson Foods, weighs in on the company’s blog: “Feeding the nation and keeping our employees healthy”.

UPDATE 2: more about the MIT study on the NYC subway as “the mother of all super-spreader events”.

The myth of the starving composer

A friend of mine was told that, basically, “you’re not Beethoven and you’re never going to make a living at composing, so stop already. Besides, even Beethoven starved”. Aside from the proper answer being Sierra Tango Foxtrot Uniform or (in Yiddish) Golf Kilo Oscar Yankee, let’s address the enduring (and pernicious) myth of the starving artist/composer.
A writer https://goinswriter.com/die/ blogs about it here, particularly focusing on Michelangelo — whose fortune in today’s terms would have been in the millions.

The most damaging myths are always those with a grain of truth in them. It is undeniably true that few if any of the great composers of your were able to make a living directly and exclusively off composition — but that didn’t mean they starved, or that they could not make a living in music!

Let’s start with (to me) the greatest of them all, J. S. Bach. As explored in great detail in Christoph Wolff’s scholarly biography, the surviving financial evidence suggests Bach’s income stream made him solidly middle-class, or even upper middle class, by the standards of his day — and all of it was related to music. His main incomes were as an organist, then as a Kapellmeister (music director — the modern concept of a conductor emerged only later), then as the Thomaskantor (music director and assistant principal of the St. Thomas High School in Leipzig). Some of these jobs included composing duties — Bach wrote several years’ worth of weekly church cantatas.
He had respectable secondary incomes as a private keyboard tutor (for which he was in high demand), as what we would today call a “consultant” on church organ construction, and even as an agent for the Silbermann family of harpsichord and fortepiano builders. (The instrument he was representing them for was an early fortepiano — giving the lie to another myth, that playing Bach on the piano is somehow inappropriate.)
But would Bach have been able to feed and house his large family on intermittent composition commissions? Or from publishing his works? The economics of the day didn’t work that way. Copyright as we understand it today didn’t really exist. (Nor did the modern conception of plagiarism, by the way — composers borrowed thematic material from each other, from folk tunes,… as a matter of course.) Music printing was a laborious and costly process that involved engraving by hand on copper plates, and only a handful of Bach’s works were printed during his lifetime. (The Art of the Fugue appeared posthumously but Bach arranged for, and subsidized, the publication while he was still alive — he clearly intended this Mount Everest of absolute music to be his artistic testament.)

So could he live well? Yes. Could he live well off music? Yes. Could he live solely from composition? No, but the very concept of a full-time composer did not exist in the day.

But what about Mozart, you say? Mozart actually made quite a bit of money off music. He had wealthy admirers, he was a keyboard virtuoso since childhood, staged operas that not only will endure when today’s richest Broadway composer will have been forgotten but were popular in their day,… and indeed ghostwrote music for wealthy would-be composers. (This is the true origin of the “Requiem” story. https://en.wikipedia.org/wiki/Franz_von_Walsegg) On the flip side, he was a spendthrift and thus perennially in debt, though his fortunes appeared to have turned around when he caught what appears to have been [http://doi.org/10.7326/0003-4819-151-4-200908180-00010] a streptococcal infection and died — again, there was no king or queen safe from that at the time.

Beethoven, to greater or lesser degree, was able to live primarily off composition. Despite his by all accounts volcanic temper and cantankerous personality, he had rich admirers. But crucially, as discussed e.g. in Jan Swofford’s biography, he would subsidize his “serious” output with volumes of song transcriptions and “bagatelles” (short, easy, inventive piano pieces playable by amateurs) that his publisher would pay good money for. Yes, even that “artiste’s artiste” would write unabashedly for the masses sometimes! (It is a measure of Beethoven’s genius, to me second only to Bach, that even these throwaway pieces contain some real gems of invention.)

Liszt gained fame and fortune as a legendary piano virtuoso (a “rock star” of his day whose “groupies” engaged in embarrassing displays) before retiring to focus full-time on composition of works more profound than the flashy showpieces he had written for his own use. Chopin, aside from a concert pianist, taught piano lessons to the rich and famous of his day for what are princely fees by any standard. Mahler never gained the esteem he has now as a composer during his lifetime, but held one of the most prestigious conductor positions of the day. (That he had to convert from Judaism to Roman Catholicism to get it is another story.) Bruckner, whose symphonies I have only recently started appreciating, enjoyed fame as an organist during his lifetime. The list is endless.

In fact, until the modern era, the performer and/or practical music educator was the norm among composers, and the full-time composer the exception. Pianist and organist Anthony Newman, in an interview in Keyboard Magazine that I read as a teenager, actually argued that classical music started becoming a sterile art form precisely when composers were no longer primarily performers.[*]

As we have seen above, the “starving artists” weren’t all that starving (some, like Handel, indeed got rich); the Great Composers, for the most part, were professional performers first; and the Professional Composer is a comparatively recent phenomenon that coincidentally (?) coincides with the decline of classical music as a living art form.

We are now living in an era where skilled amateurs can put their music, writings, or other creative works in front of a global audience for comparatively modest investments. The challenge now has shifted to bringing it to the attention of people, to make it stand out from the crowd. Conventional agents and publishing houses are increasingly becoming redundant or even irrelevant to the process, though I can see the role of a publicist transforming, rather than disappearing.
However, the “YouTube/SoundCloud economy”, where you compete less for money and for people’s attention and time, in some ways will be an interesting throwback to aspects of yesteryear’s composers. Bands today often don’t make any real money off albums due to illicit downloading and the overheads of legacy record labels — it is in live shows that the real money is nowadays, as people are clearly still willing to shell out money for “the live experience”. Had Bach or Handel lived today, they would probably each have millions of followers on YouTube (and have millions of people illegally downloading their music) — but Handel got rich staging his own operas and oratorios then, and would likely have to do so now. Bach would likely be able to travel in style from one sold-out-in-hours gig to the next — but he likely would be touring if he wanted more money than a faculty appointment could provide. Of course, once they got famous in our fictional world, a billionaire with good musical taste would be willing to bankroll them, but I can’t see Handel giving up the stage. Bach perhaps, because as much as he loved the good life, this deeply religious man ultimately wrote for an audience of One.

I would counsel my friend to “Keep calm and carry on”.

[*] The case of Jean-Philippe Rameau is somewhat peculiar. He first gained recognition as a music theorist (his Treatise on Harmony is a milestone in the field to this day) and considered himself a music scholar first and foremost. But he worked as a church organist for over two decades after succeeding his father, and ultimately gained fame as an opera and ballet composer, conducting his own works. Ironically, the greater ease of printing a book (rather than sheet music) in the age before digital typesetting may have contributed to his early reputation.

Parkinson’s Law of Triviality

This oldie but goodie has surely been shared many times, but it’s nice to see this particularly pithy formulation. C. Northcote Parkinson was a naval historian, who unintentionally became something of a management theorist through his trenchant observations of how large bureaucracies work.

In the third chapter [of the book Parkinson’s Law, and Other Studies in Administration], “High Finance, or the Point of Vanishing Interest”, Parkinson writes about a fictional finance committee meeting with a three-item agenda: The first is the signing of a £10 million contract to build a [nuclear] reactor, the second a proposal to build a £350 bicycle shed for the clerical staff, and the third proposes £21 a year to supply refreshments for the Joint Welfare Committee.

1. The £10 million number is too big and too technical, and it passes in two and a half minutes. One committee member proposes a completely different plan, which nobody is willing to accept as planning is advanced, and another who understands the topic has concerns, but does not feel that he can explain his concerns to the others on the committee.
2. The bicycle shed is a subject understood by the board, and the amount within their life experience, so committee member Mr Softleigh says that an aluminium roof is too expensive and they should use asbestos. Mr Holdfast wants galvanised iron. Mr Daring questions the need for the shed at all. Holdfast disagrees. Parkinson then writes: “The debate is fairly launched. A sum of £350 is well within everybody’s comprehension. Everyone can visualise a bicycle shed. Discussion goes on, therefore, for forty-five minutes, with the possible result of saving some £50. Members at length sit back with a feeling of accomplishment.”
3. Parkinson then described the third agenda item, writing: “There may be members of the committee who might fail to distinguish between asbestos and galvanised iron, but every man there knows about coffee – what it is, how it should be made, where it should be bought – and whether indeed it should be bought at all. This item on the agenda will occupy the members for an hour and a quarter, and they will end by asking the secretary to procure further information, leaving the matter to be decided at the next meeting.”

Parkinson, in the book, considers whether the discussion time will in fact keep going up as the amounts become even more trivial, reaching infinity for an amount of zero. He concludes that at some point, people will decide the sum is beneath their notice and tune out altogether.