COVID19 update, June 30, 2020: droplet and aerosol transmission; herd immunity requires as little as 20%?

Been a very busy day at work, but let me just share with you two things:

(a) a long essay that Jeff Duntemann drew my attention to:

Aerosols, Droplets, and Airborne Spread: Everything you could possibly want to know by Justin Morgenstern MD, an emergency physician located in the greater Toronto area.

The essay is long but very much worth your while.

(b) Coronavirus: could it be burning out after 20% of a population is infected? We pointed earlier to a preprint that showed that, if susceptibility to the infection isn’t assumed to be all or nothing, that this leads to a second-order mathematical model that predicts much lower herd immunity thresholds than the common first-order model. See also (h/t: masgramondou): https://judithcurry.com/2020/05/10/why-herd-immunity-to-covid-19-is-reached-much-earlier-than-thought/ 

But it is unlikely that lockdowns alone can explain the fact that infections have fallen in many regions after 20% of a population has been infected – something that, after all, happened in Stockholm and on cruise ships. 

That said, the fact that more than 20% of people have been infected in other places means that the T-cell hypothesis is unlikely to be the sole explanation either. Indeed, if a 20% threshold does exist, it applies to only some communities, depending on interactions between many genetic, immunological, behavioural and environmental factors, as well as the prevalence of pre-existing diseases. 

Understanding these complex interactions is going to be necessary if one is to meaningfully estimate when SARS-CoV-2 will burn itself out. Ascribing any apparent public health successes or failures to a single factor is appealing – but it is unlikely to provide sufficient insight into how COVID-19, or whatever comes next, can be defeated.

COVID19 update, June 29, 2020: March 2019 sample in Barcelona? Matt Margolis on lockdowns; Germans flock to Baltic beaches; 2nd wave in Israel

(1) Apparently, a sample of sewer water in Barcelona from March 2019 (!) tested positive for SARS-nCoV-2. Dr. John Campbell comments:

I am somewhat skeptical though.

(2) Matt Margolis blogs about lockdowns and argues they were a mistake. He also goes into the current spike, which does not seem to be accompanied by a spike in mortality (allowing for a 2-3 week lag).

Conventional wisdom suggests that a spike in cases should result in a spike in deaths, but that has not panned out. The protests and riots following George Floyd’s death have been going on for nearly a month now. Surely a spike in deaths should shave occurred by now. But so far, it hasn’t. 

Why not? 

According to Justin Hart, an information architect and data analyst from San Diego, “who” gets the virus is just as important as “how many” get the virus. “Right now the average age of infected cases has dropped nearly 20 years,” Hart told PJ Media. […]

According to the CDC’s current best estimate, the fatality rate of the coronavirus for symptomatic cases only are as follows:

0-49 years old: 0.05%
50-64 years old: 0.2%
65+ years old: 1.3%
Overall ages: .4%

As I mentioned the other day, it’s the same story in the UK, where mortality of COVID-19 hospital admittees has dropped from 6% to 1.5%.

(3) “Sunlight is the best disinfectant” — literally, in this case. 

In Germany, however, Die Welt worries (in German) about the epidemiological situation as tourists hit the Baltic Sea resorts 

(4) Israel has apparently a genuine 2nd wave on its hands. As in (2), it seems that cases are much younger than in the past. This infographic from the Israel COVID19 dashboard of the Ministry of Health makes this very clear. (Note that this is all documented cases — if the window were limited to those diagnosed in the past month, the distribution would be even more lopsided.)

[left=women, right=men, diffuse background=population pyramid, crisp bars=COVID19 case distribution]

Tomorrow school ends for kindergarten and elementary schools; junior high and high schools already finished. 

There were “corona cabinet” meetings yesterday and today. A second lockdown was dismissed out of hand, as were less restrictive closures, since “the economy won’t survive those blows”. For now, distance restrictions and masks remain mandatory (if seemingly honored more in the breach than the observance), and these will be enforced more vigorously. Some restrictions on attendance at public gatherings were re-introduced. 

Meanwhile, mothballed COVID-19 wards in various hospitals have been reopened. The general atmosphere in the healthcare system, as far as I can tell, is more relaxed than in March: more treatment options exist, more is knownabout how to manage moderate and severe cases, and younger patients typically mean mild cases that resolve on their own.

(5) I can’t add much to Instapundit’s response to Dr. Fauci’s complaint about the “anti-science bias in the US”.

If scientists were more pro-science, maybe the public would be. But when scientists are happy to subordinate science to politics or expediency — as the public health community has shown itself to be with masks and with its endorsement of mass protests — why should anyone trust them?

COVID19 update, June 27, 2020: The Economist on how COVID-19 changed the office; reduced hospital fatality rates in the UK; initial infection rates may have been 80 times higher than reported

(1) The Economist has a video on how COVID-19 is changing the office building as we know it. Working from home used to be the exception — companies insisted that you show up in the office even for work that can be done from home very well

Now COVID-19 has forced companies to make a virtue of necessity — and it turns out this works pretty well. The video claims that 47% of all existing jobs in Switzerland can be done from home, with somewhat lower percentages for other developed economies, but much lower percentages for developing countries.

And guess what: considering how expensive office space in premium locations is (downtown Hong Kong, with about $250/mo/square meter, probably takes the case), companies can save a ton of money by letting WFH-feasible jobs be done from home and downsizing their office locations.

This will have a ripple effect: a WSJ journalist interviewed in the video claims that every Manhattan office job created employment for 5 people in the service industry (bars and restaurants, custodial,…) 

Of course, one man’s meat is another man’s poison, so it is quite possible that the lost jobs catering to downtown office worker may be partly or even wholly offset by other jobs created elsewhere — as people working from home will want to upgrade their housing arrangements, or will have more disposable income to spend on family amenities.

I would not say that COVID-19 will bring the end of the Dilbert cube farm as we know it: simply that it triggered a transformation that was waiting to happen, only delayed by managerial inertia.

(2) There are reports from various countries that hospital mortality rates have dropped considerably from the peak of the infection. The Daily Telegraph reports that mortality of COVID19 patients admitted to English hospitals has dropped fourfold, from 6% in April (the peak of the epidemic there) to 1.5% now. A number of explanations are proffered:

• Doctors have gotten better at managing the disease and mitigating its severity
• Hospitals have enough capacity now that milder cases can now be admitted that would have been sent home earlier: as these mild cases almost invariably recover, this drives down the statistics
• The most vulnerable older people either have already died or recovered, or we have simply gotten better at shielding the elderly from infection. 
• [not in the article] the better, sunnier weather reduces vitamin D deficiency

(2b) [Hat tip: Erik W.]

An epidemiological study from Penn State U. suggests that the initial COVID19 infection rate in the US may have been about 80 times the officially reported one. The paper can be read directly here:

http://doi.org/10.1126/scitranslmed.abc1126

Quoting from the abstract:

Detection of SARS-CoV-2 infections to date has relied heavily on RT-PCR testing. However, limited test availability, high false-negative rates, and the existence of asymptomatic or sub-clinical infections have resulted in an under-counting of the true prevalence of SARS-CoV-2. Here, we show how influenza-like illness (ILI) outpatient surveillance data can be used to estimate the prevalence of SARS-CoV-2. We found a surge of non-influenza ILI above the seasonal average in March 2020 and showed that this surge correlated with COVID-19 case counts across states. If 1/3 of patients infected with SARS-CoV-2 in the US sought care, this ILI surge would have corresponded to more than 8.7 million new SARS-CoV-2 infections across the US during the three-week period from March 8 to March 28, 2020. Combining excess ILI counts with the date of onset of community transmission in the US, we also show that the early epidemic in the US was unlikely to have been doubling slower than every 4 days. Together these results suggest a conceptual model for the COVID-19 epidemic in the US characterized by rapid spread across the US with over 80% infected patients remaining undetected.

Note that a “Dunkelziffer” of 80:1 is in the 50:1  – 85:1 range the [much-maligned] original version of the Santa Clara serological study (Ioannides et al.) had.

(3) “Covid toes” may actually not be a COVID-19 symptom or sequel after all, but simply result from lack of physical activity , reports UPI.

The “symptom” mirrors that of a condition called Chilblains, or perniosis, a painful inflammation of the small blood vessels in the skin that occurs after repeated exposure to cold air, they said.

(4) [Hat tip: Jeff Duntemann] A retired anesthesiologist on masks:

To protect yourself, you need an N95 respirator mask that is properly fitted.  Then you need to re-sterilize it every four hours using UV light or properly dispose of it and start over with a new one.  That is too expensive for most people.

The outside world is the safest place you can be.  The state of Florida has zero cases of COVID-19 that can be traced to outside transmission.  During the day, solar UV kills all viruses very quickly, and there’s always enough air movement to disperse aerosols, making them non-infective.  It has become clear that virtually all cases have been spread in closed spaces with prolonged (>10 minute) exposure.  And as the studies I’ve cited show, other than N95s, masks are no help there.  For that matter, six-foot spacing doesn’t help, either, since the aerosols that transmit the virus aren’t adequately dispersed.

COVID19 update, June 25, 2020: Greek colchicine trial; Dr. Campbell on long-term sequelae and home antibody testing

(1) It seems that steroids are not the only low-cost anti-inflammatories that reduce COVID19 aggravation and mortality. In two previous posts, back in April and again last week, I mentioned clinical trials with the ancient anti-inflammatory colchicine. 

Results from a randomized clinical trial in Greece were just published in JAMA (the Journal of the American Medical Association). The sample is small (since fortunately for them, Greece had a pretty mild COVID19 season) but there are some statistically significant results.

http://doi.org/10.1001/jamanetworkopen.2020.13136 

In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece.

Intervention  Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks.

Main Outcomes and Measures  Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale[*], ranging from able to resume normal activities to death.[…]

Results  A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. […] The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003).

 

This is a small-sample study, but with definitely a promising result. [Full disclosure: I’ve taken colchicine on and off for gout (its primary indication), for which it is very effective — I have had essentially no side effects from the drug.]

(2) Dr. John Campbell here discusses long-term sequelae for people who survive not-so-mild cases of COVID19.

But at 22:10, he also shows a demonstration of a home antibody testing kit.

 

[*] Elsewhere in the paper, the 7-step ordinal scale is defined as follows:

1, ambulatory, normal activities;

2, ambulatory but unable to resume normal activities;

3, hospitalized, not requiring supplemental oxygen;

4, hospitalized, requiring supplemental oxygen;

5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both;

6, hospitalized, requiring extracorporeal membrane oxygenation, invasive mechanical ventilation, or both;

7, death.

COVID19 update, June 24, 2020: vaccines progressing faster than expected; more on dexamethasone and other steroids

(1) Chemical and Engineering News, the house organ of the American Chemical Society, has a cover story about current progress in vaccine efforts.

Large trials this summer and fall could provide the first evidence that some of the experimental COVID-19 vaccines are working. AstraZeneca, which is developing an adenoviral vector vaccine designed at the University of Oxford, is recruiting 10,000 people in the UK, 30,000 people in the US, and potentially 2,000 people in Brazil for its Phase III study to determine if the vaccine is effective. If the trial is successful, AstraZeneca says, it could start distributing the vaccine as early as September in the UK and October in the US.
 
Moderna plans to begin a 30,000-person Phase III study of its messenger RNA (mRNA) vaccine in July. The firm is working with the contract manufacturer Lonza to produce 500 million doses or more per year.

And J&J, which like AstraZeneca is developing an adenoviral vector vaccine, says it will begin its first clinical trial in the second half of July—two months earlier than anticipated. The trial will test the vaccine in 1,045 healthy volunteers in the US and Belgium. J&J is also trying to move faster on planning for its larger trials.

The Chinese companies Sinovac and China National Pharmaceutical Group—also known as Sinopharm—are prepping for Phase III studies of their vaccines outside China. Both firms are developing vaccines made from chemically inactivated SARS-CoV-2. They say people receiving their vaccines in Phase II studies developed neutralizing antibodies to the virus, but the data have not been published.

Pending a vaccine, monoclonal antibodies “could be a bridge”.

Lilly was the first company to begin clinical trials of monoclonal antibodies, discovered by the Canadian company AbCellera Biologics and the Chinese firm Shanghai Junshi Biosciences. It took only about 90 days from the start of AbCellera’s discovery program to the first injection of the antibody in a clinical trial.
“Typically, that process could take between 1 1/2 to 2 years minimum, so doing it in 3 months is extraordinary,” says Janice Reichert, executive director of The Antibody Society, a trade organization.
Others are also moving fast. Regeneron has begun two clinical trials of an experimental therapy that includes two monoclonal antibodies that target SARS-CoV-2. Tychan says it has begun clinical trials of its antibody in China.
 
By Reichert’s estimation, there could be upward of 20 SARS-CoV-2 antibody programs in clinical studies by the end of the year, and it should not take long to determine if these drugs are effective. Lilly says it could have data by the end of the summer. “The readout is pretty quick with COVID-19,” Reichert says. “You either get better or you don’t.”

(2) Dr. Seheult has an additional video on dexamethasone, and how this did not come out of nowhere, but built on early results from ad hoc, unsystematic treatment with various steroids. 

The received wisdom was to avoid administering steroids in respiratory infections, as they put a damper on the immune system and make the patient more vulnerable to bacterial superinfection. Especially in a hospital setting, with multiple-drug-resistant strains endemic, this is a major concern: most seasonal flu victims actually die from secondary infections rather than the influenza virus directly.

However, as doctors at hospitals treating COVID-19 patients started recognizing the signs of ARDS (acute respiratory distress syndrome) and cytokine storm, they started trying various immunomodulators, of which steroids are the most readily available. Since these earliest applications were often to the patients in greatest distress, results skewed negatively due to selection bias.

In early May, a preprint was released of a study in Michigan that showed a short course of methylprednisolone IV significantly reduced (p=0.005) escalation of disease severity, and reduced median length of hospital stay from 8 to 5 days (p=0.001). In plain English, p=0.005 means there is only a 0.05% probability, or 1 chance in 200, that the difference is due to the luck of the draw. With p=0.001, we’re talking 1 chance in 1,000 the difference is due to coincidence.

https://doi.org/10.1101/2020.05.04.20074609

Then of course the famous Oxford “Recovery” trial of dexamethasone happened and was published. This has a large, careful constructed sample and a solid control arm. Recapping from our earlier post on the subject, 

Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14).

p=0.0003, in plain English, means there are three chances in ten thousand that the difference is due to coincidence, p=0.0021 corresponds to one such chance in five hundred, while p=0.15 is a bit more than one chance in seven. 

What is the likelihood that a patient not on a ventilator needs to be put on a ventilator later? That is actually also fairly significantly lower on the steroid  (p=0.021, or 1:50 odds of this being coincidence).

This is likely to change treatment everywhere: dexamethasone is quite cheap and readily available, and in fact can even be administered orally. Better still: the mechanism of action is fairly clear: reducing the inflammatory reaction that has the patients’ own immune systems “killing the patients in order to save them”. Antivirals like remdesivir appear to be more effective in earlier disease stages: a synergy between the two can hopefully do a lot of good. (Alas, remdesivir is fairly difficult to synthesize and requires IV administration.)

 

 

COVID19 update, June 23, 2020:Dr. John Campbell guest reports from Israel; Dr. Seheult on dexamethasone

Been an intense work day. Let me just share two videos:

(a) Dr. John Campbell has a guest on from Israel

(b) Dr. Seheult on the latest dexamethasone findings

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

Very briefly after a long workday.

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

 

 

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

 

 

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

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

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

COVID19 update, June 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, June 17, 2020: Colchicine redux; miscellaneous updates

(1) Back in April, Mrs. Arbel alerted me to an item about a clinical trial for the anti-inflammatory drug colchicine (which I’ve been taking on and off for gout – side effect of a low-carb, high-protein diet). Now a team at Hadassah Hospital (the main teaching and research hospital of Hebrew U. of Jerusalem) believes it has figured out what causes the rogue blood clots associated with severe COVID-19. 

Hadassah researchers discovered that the patients who form these fatal clots have an increased level of alpha defensin protein in their blood, explained[Israeli Arab] Dr. Abd Alrauf Higavi, who directs a lab at Hadassah and has been studying blood clots for 30 years. 
“Patients with mild symptoms have a low concentration of alpha defensin,” he said. “Patients with strong disease symptoms have high levels. The people who die have very high levels.”

The Hadassah team studied more than 700 blood samples from 80 patients who were admitted to the medical center during the first peak of the coronavirus outbreak in Israel. The results show that alpha defensin speeds up blood clot formation, which can cause pulmonary embolism, heart attacks and stroke. In addition, when blood clots form in the alveoli, whose function it is to exchange oxygen and carbon dioxide molecules to and from the bloodstream, this can lead to respiratory distress and eventually intubation.

And guess what they offer as the solution?

Colchicine is an approved drug used in the prevention and treatment of gout attacks, caused by too much uric acid in the blood.
Higavi said they have completed testing colchicine on mice and found that it successfully inhibited the release of alpha defensin. Now, they are waiting for the necessary approvals to test it on human coronavirus patients. 
The researcher said that clinical trials would look at use of the drug both for severe cases and administering it to patients with mild or moderate symptoms to see if it will help decrease the chances of their developing a severe case of the disease. 
“The drugs available today in the blood-thinning market do not fully address this clotting, since its mechanism differs from the mechanisms for which these drugs currently exist,” Higavi said. “Resources should be diverted to finding a suitable drug for coronavirus patients.”

(2) Miscellaneous updates:

Israeli artificial intelligence firm offering an early COVID-19 detection solution gets emergency authorization from the FDA. 

Kamada seeks Phase 1/2 clinical trial for passive vaccine

De Standaard reports that Janssen Pharmaceutica, a wholly-owned subsidiary of Johnson & Johnson, is recruiting 500 volunteers for a phase 1 trial and will later look for an infested area to carry out a 20,000 subject trial (half vaccinated, half placebo).

In the US Senate, McCaul Report  “Chinese cover-up turned local epidemic into global pandemic”.

Australia puts scrutiny on China’s cat’s paws.

European Commission wants to forestall “bargain-hunting” takeovers of distressed companies by Chinese state-backed investors, reports De Standaard (in Dutch).

 

COVID19 update, June 16, 2020: Blue-chip Oxford trial finds inexpensive steroid dexamethasone saves lives in severe COVID-19 cases; flare-ups in Israel and in China

(1) [Hat tip: Yves not-Cohen]: via De Standaard and the BBC, Oxford University reports a breakthrough in the management of severe COVID-19 cases: https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf

I have blogged earlier about anecdotal reports that steroids (for the group I was quoting, methylprednisolone) were being used in an attempt to hold “cytokine storm” at bay, and intuitively this makes a lot of sense. But now we have a large-scale clinical trial to back it up.

A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone. Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%). Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14). Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone. Given the public health importance of these results, we are now working to publish the full details as soon as possible.

In plain English, p=0.0003 means there are three chances in ten thousand that the difference is due to coincidence , p=0.0021 that there are 2.1 chances in a thousand of this happening. That the steroid would have no benefit in patients who show no signs yet of “cytokine storm” makes perfect sense.

The study’s authors tout this as the first drug that actually saves lives. Indirectly, Remdesivir and other antivirals may do so if given early in the disease progression, by preventing escalation to cytokine storm: once you get there, you have missed the boat for antivirals and need to focus on stopping the patient’s immune system from killing him.

That dexamethasone is a dirt-cheap drug that has been in common use for decades is of course a nice bonus.

(2) Related, via The Epoch Times (an expat Chinese newspaper fiercely opposed to the regime) a report by the British Heart Foundation about TRV027, an experimental drug by Trevena that restores the angiotensin II vs. angiotensin 1-7 balance (which the virus disrupts through binding to ACE 2 receptors) and thus tries to prevent excessive blood clotting at the source.

Also related, US Senate testimony  by Pierre Kory MD of the COVID19 Critical Care Group.

 

(3) Israel, after a lull and after essentially fully reopening, is now seeing a flare-up of about 200 cases per day. In part this can be ascribed to more intensive testing efforts: past data indicate we had about 10 undocumented asymptomatic or mild cases for each documented case.  (Yesterday, 13,425 were tested, of which 196 found positive.)

The head of the research division of the Maccabi HMO (one of the four authorized Health Maintenance Organizations in Israel, and one of the “big three”) explains to The Times Of Israel that this time around, most of the cases are children or young people (which are less vulnerable), and that many of the children are asymptomatic.

 

In Tel Aviv, which is seeing the fastest spread of the virus, some 57 percent of Maccabi members who tested positive in June are aged 18 or under, Anat Ekka-Zohar told The Times of Israel. There is a similar pattern in other central Israeli cities where cases are growing, she said. In Peta[c]h Tikva the figure is 77%, in Jaffa 60% and in Bnei Brak 43%.

Lots of the current adult carriers are aged 45 or under, Ekka-Zohar said. Some 73% of Maccabi members nationally who tested positive in June are 45 or under, and in Tel Aviv, the figure is 79%.

Maccabi, which is responsible for the health of 2 million Israelis, says that just 1.3% of the people it found to be infected in June are aged 75 or older, Ekka-Zohar said.

Looking at the figure for the 65-plus age group, which is considered the most at-risk of serious illness or death if infected, Ekka-Zohar said it stands at 6.7% for June cases. In April, that age group accounted for around 12% of Maccabi’s cases, she added.

The fact that the most vulnerable aren’t being infected in large numbers bodes well, Ekka-Zohar said, commenting: “It’s not going to provoke a crisis in terms of the number of hospitalizations or in terms of ventilators.”

 

(H/t: Mrs. Arbel.) A somewhat PG-13 rated piece of local humor about masks: the caption says “wearing your mask like thisis like wearing your underpants like that. [And underneath] Please wear your mask correctly.”

(4) “Nothing to see here, move along.” The regime is now blaming “European salmon” for a new coronavirus outbreak in Beijing?! Yeah right — if you believe that, I have some beachfront land in Arizona for sale. Most likely, this is just the 2nd wave of the epidemic they claimed they had under full control. Remember this piece of advice by a Hong Kong resident (warning: language alert).

COVID19 update, June 15, 2020: Ivermectin redux; “modelers have failed’

(1) The Jerusalem Post interviews Prof. Eli Schwartz, the head of the tropical medicine department at Tel HaShomer hospital in the Tel Aviv borough of Ramat-Gan (one of the “Big Four” research and teaching hospitals in Israel, together with Sourasky/Ichilov in central Tel Aviv, Hadassah in suburban Jerusalem, and Rambam/Maimonides in Haifa) about a drug repurposing study involving ivermectin (an antithelmintic/anti-worm drug familiar to veterinarians and travelers to tropical countries, but not to most physicians in Western countries.

The discoverers of this drug shared the 2015 Nobel Prize in Medicine and Physiology. With the discoverers of the next-generation antimalarial artemisinin. An Australian study, part of an effort to find repurposeable already-approved drugs, found a few months ago that ivermectin liquidates the virus in vitro (i.e., in a test tube), which prompted several clinical trials:

https://doi.org/10.1016/j.antiviral.2020.104787

Here is a preprint about a retrospective, open-label study in several Dade County, FL hospitals (i.e., the Miami area):

https://www.medrxiv.org/content/10.1101/2020.06.06.20124461v2

280 patients with confirmed SARS-CoV-2 infection (mean age 59.6 years [standard deviation 17.9], 45.4% female), of whom 173 were treated with ivermectin and 107 were [given] usual care were reviewed. 27 identified patients were not reviewed due to multiple admissions, lack of confirmed COVID results during hospitalization, age less than 18, pregnancy, or incarceration.

Univariate analysis showed lower mortality in the ivermectin group (15.0 % versus 25.2%, OR 0.52, 95% CI 0.29-0.96, P=.03). Mortality was also lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%, OR 0.15, CI 0.05-0.47, P=.001), but there was no significant difference in successful extubation rates (36.1% vs 15.4%, OR 3.11 (0.88-11.00), p=.07). After adjustment for between-group differences and mortality risks, the mortality difference remained significant for the entire cohort (OR 0.27, CI 0.09-0.85, p=.03; HR 0.37, CI 0.19-0.71, p=.03)

In plain English, p=0.03 means there’s a 3% chance that the difference is due to coincidence, while p=0.001 means there is just one chance in a thousand this is a coincidence. 

Considering this is a cheap and widely available drug, this sounds like great news.

(2) In a blog post at the IIF (International Institute of Forecasters), Prof. John Ioannides of Stanford and two colleagues from Northwestern U. and U. of Sydney say bluntly “Forecasting for COVID-19 has failed”. They go on to analyze the failures in detail and to conjecture reasons for them — which go further and deeper than “fog of war”. Read the whole thing — I can’t do it justice with selective quoting. Just a taste:

Failure in epidemic forecasting is an old problem. In fact, it is surprising that epidemic forecasting has retained much credibility among decision-makers, given its dubious track record. Modeling for swine flu predicted 3,100-65,000 deaths in the UK [11]. Eventually only 457 deaths occurred [12]. The prediction for foot-and-mouth disease expected up to 150,000 deaths in the UK [13] and led to slaughtering millions of animals. However, the lower bound of the prediction was as low as only 50 deaths [13], a figure close to the eventual fatalities. Predictions may work in “ideal”, isolated communities with homogeneous populations, not the complex current global world.[…]

Let’s be clear: even if millions of deaths did not happen this season, they may happen in the next wave, next season, or with some new virus in the future. A doomsday forecast may come handy to protect civilization, when and if calamity hits. However, even then, we have little evidence that aggressive measures which focus only on few dimensions of impact actually reduce death toll and do more good than harm. We need models which incorporate multicriteria objective functions. Isolating infectious impact, from all other health, economy and social impacts is dangerously narrow-minded. More importantly, with epidemics becoming easier to detect, opportunities for declaring global emergencies will escalate. Erroneous models can become powerful, recurrent disruptors of life on this planet. Civilization is threatened from epidemic incidentalomas.

(3) In brief:

• A 26-year old without pre-existing conditions got Kawasaki’s Disease as a COVID-19 complication and this became our youngest victim 
• Beijing reinstates lockdowns following resurgence
• As Americans return to offices after long lockdowns, they are told to beware of Legionella in stagnant water (h/t: littleoldlady)
• Of the Israelis laid off due to COVID-19, about two-thirds are still drawing unemployment benefits, the remaining third are working again 
• FDA pulls emergency authorization for hydroxychloroquine, just as De Standaard (in Dutch) reports that it was used, open-label, on at least 5,000 COVID-19 patients in Belgium
• The paper also includes a brief piece on ’the druid” Prof. Didier Raoult, the French tropical medicine institute director who’s been plugging his treatment with HOcq, zinc, and azithromycine. Raoult is portrayed there as a hero of the political right (un soupir de lassitude cosmique/sigh of cosmic weariness) — especially after the right-wing mayor of Marseiile got better from COVID-19 under Raoult’s treatment.

COVID19 update, June 14, 2020: avoiding the Three C’s of Transmission; most asymptomatic cases remain asymptomatic

Busy workday, so just some quick updates:

(1) (hat tip: Masgramondou): Are Technica: “Just 10-20% of cases are behind 80% of transmission” 

Benjamin Cowling, a Hong Kong-based epidemiologist and biostatistics expert, agrees. Cowling and colleagues recently studied transmission in Hong Kong, finding superspreading events drove local transmission. In a recent op-ed, he and a colleague argue that public health policies aimed at stopping the pandemic should focus on stopping superspreading.

“The epidemic’s growth can be controlled with tactics far less disruptive, socially and economically, than the extended lockdowns or other extreme forms of social distancing that much of the world has experienced over the past few months,” the researchers wrote

In an email to Ars, Cowling fleshed out this idea a bit, noting that “measures that specifically target superspreading are those that reduce or prevent large gatherings of people,” such as those to reduce the density of people in schools and workplaces.

Measures not specifically targeted to superspreading, he noted, “are those like asking everybody to stay at home as much as they can, despite many workplaces and social settings not being places that superspreading could occur.”

In the op-ed, Cowling noted that Japan—which has been relatively successful at managing the pandemic—has employed an anti-superspreading policy called [“the Three Cs Of Transmission”]: Avoid (1) Closed spaces with poor ventilation, (2) Crowded places, and (3) Close-contact settings, such as close-range conversations. The risk for superspreading is highest in situations with all three Cs.

[…]Cowling and his colleagues’ analysis has been posted online but has not yet been peer-reviewed or published in a scientific journal. But, they note, their findings from Hong Kong aren’t unique. For instance, a study published in the Lancet in April, which looked at transmission of SARS-CoV-2 in Shenzhen, China, found that just around 9 percent of cases accounted for 80 percent of transmission. And a modeling study from researchers in London likewise found that just about 10 percent of cases may account for 80 percent of transmission.

Read the whole thing.

(2) via Instapundit, this report by UPI quoting this letter to the New England Journal of Medicine from a Japanese team:

http://doi.org/10.1056/NEJMc2013020

The outbreak of coronavirus disease 2019 (Covid-19) on the cruise ship Diamond Princess led to 712 persons being infected with SARS-CoV-2 among the 3711 passengers and crew members, and 410 (58%) of these infected persons were asymptomatic at the time of testing[….] A total of 96 persons infected with SARS-CoV-2 who were asymptomatic at the time of testing, along with their 32 cabinmates who tested negative on the ship, were transferred from the Diamond Princess to a hospital in central Japan between February 19 and February 26 for continued observation. Clinical signs and symptoms of Covid-19 subsequently developed in 11 of these 96 persons, a median of 4 days (interquartile range, 3 to 5; range, 3 to 7) after the first positive polymerase-chain-reaction (PCR) test, which meant that they had been presymptomatic rather than asymptomatic.

[…] The group of persons with asymptomatic SARS-CoV-2 infection consisted of 58 passengers and 32 crew members, with median age of 59.5 years (interquartile range, 36 to 68; range, 9 to 77). A total of 24 of these persons (27%) had coexisting medical conditions, including hypertension (in 20%) and diabetes (9%). The first PCR test at the hospital was performed a mean of 6 days after the initial positive PCR test on the ship. The median number of days between the first positive PCR test (either on the ship or at the hospital) and the first of the two serial negative PCR tests was 9 days (interquartile range, 6 to 11; range, 3 to 21), and the cumulative percentages of persons with resolution of infection 8 and 15 days after the first positive PCR test were 48% and 90%, respectively. The risk of delayed resolution of infection increased with increasing age.

In this cohort, the majority of asymptomatically infected persons remained asymptomatic throughout the course of the infection. The time to the resolution of infection increased with increasing age.

 

(3) UnHerd: so where did the virus really come from? Dogmatic answers do not behoove a scientist, as the writer rightly argues. On the other hand, extraordinary claims (e.g., a genetically engineered virus) require extraordinary proof. Either way, we need all the evidence we can get. Read the whole article.

This is in the realm of speculation, but I’ve been wondering: what if, after the outbreak began, local officials panicked thinking this may be a human-“improved” virus that had escaped from the WiV, then calmed down once it became clear it was “only” another novel coronavirus. That would explain some of the skittish behavior in the very beginning, the destruction of samples,…  

ADDENDUM: yes, public health experts are undermining themselves by U-turning on recommendations for political expedience. 

And Insta snarks “nothing to see here, move along”: Parts of Beijing locked down due to fresh virus cluster

ADDENDUM 2: Israeli public health expert on what we might face in the winter 

COVID19 update, June 13, 2020: Belgium takes a breather; the Jewish community of Antwerp; High-fructose corn syrup

 

(1) Belgium for a stretch has had the highest per capita COVID19 mortality in the world (except for the microstate of San Marino — beware of statistics of small numbers), with almost 10,000 dead out of a population of about 11 million. But now it seems to have turned the corner at last—daily dead are in the 10 range, down from 2-300 at the peak of the epidemic. 

So the chair of the Corona Committee, virologist Steven De Gucht, gave his last of 54 press conferences for now, looking back at the past three months. “As quickly as the dark clouds gather, just as quickly can the sun break through again,’ Van Gucht said somewhat emotionally. This is the last press conference. We can let go of the reins a little. We’ve grabbed the virus by the neck and extinguished fires. It is clear that nature can be very harsh.” Future updates will be via weekly press releases, at least until (if ever) there is a second wave.

Current COVID19 measures are detailed on a dedicated website in four languages, including in (fairly idiomatic) English. At this point, all stores are open (night stores until 1am), as are (with capacity restrictions) restaurants with table service and bars. Sports teams, musical ensembles, and theater group may practice but not yet perform for an audience: starting July 1, audiences of up to 200 are permitted (which works for the local equivalent of off-Broadway theater and for junior league soccer teams). 

(2) Also in Belgium, in an area about six square blocks by the Antwerp railway station, is the Diamond District, home to about 20,000 mostly Orthodox or Chareidi (“ultra-Orthodox”) Jews. This community has given Antwerp the nickname ‘Jerusalem on the Scheldt’ in some circles. The Jerusalem Post looks at how this community has weathered the COVID19 storm: fairly well, all told. “The community projected in March that 85% of its members could contract the coronavirus because of its close conditions and frequent social interactions, and that over 500 could die. A communal taboo about dealing with the virus, which some labeled as a scourge of the secular world, added to the danger.” In the event, only 11 (eleven) community members succumbed to the virus, all elderly and/or with major pre-existing conditions. 

 

The community […] at first downplayed the danger of the virus […] but […]  took swift action following the death rate projection, implementing strict social distancing measures that included the closure of all synagogues on March 13 — five days before federal authorities imposed a nationwide lockdown. 
 
“It’s just a few days, but with a pandemic that grows exponentially it was a crucial early step,” said [Shlomo] Stroh, who was involved in the decision-making process led by the city’s chief rabbi, Aaron Schiff, and the city’s beit din, or rabbinical court. 

Getting the Orthodox Jewish community of Antwerp to adhere to social distancing was a “gradual process,” according to Claude Marinower, an alderman in charge of the city government’s communications efforts, among other portfolios. 
 
“At first there was some pushback” from some community members against the closure of synagogues, said Marinower, who is Jewish but is not Orthodox. But “there was more cooperation as the dimensions of the pandemic emerged — and especially in Belgium, where about 10,000 people have died of the coronavirus.” 
 
“When rabbis issued strong instructions against gatherings, it was accepted by all,” Marinower said.
 
Michael Freilich, an Orthodox Jewish lawmaker from Antwerp who serves in the federal parliament, also attributed the low death rate among Jews to a combination of rabbinical leadership and authorities’ strict enforcement. Together, he told JTA, “it meant we were saved from disaster.”

With the fairly narrow streets inside the district, a creative solution to communal prayer was found: a cantor would lead the service from the street and worshipers would join in from the balconies. Some non-Jewish neighbors lodged police complaints about the noise, but others welcomed the relief from the silence during the lockdown as well as “the chance to hear what goes on inside the synagogues”. (I would imagine that anybody who has serious issues with Jews would not voluntarily live in an area of Antwerp that is best described as an urban shtetl.)

 

(3) Roger Seheult MD has videoblogged extensively on the benefits of vitamin D and zinc for the immune system generally and during the COVID-19 epidemic in particular, as well as the value of the antioxidant and mucolytic NAC (N-acetylcysteine) as a food supplement.  This time, however, he talks about something to avoid for a change: fructose and specifically high-fructose corn syrup.

http://doi.org/10.3390/nu9040405

 

Diabetes prevalence was 20% higher in countries with higher availability of HFCS compared to countries with low availability, and these differences were retained or strengthened after adjusting for country-level estimates of body mass index (BMI), population and gross domestic product (adjusted diabetes prevalence=8.0 vs. 6.7%, p=0.03; fasting plasma glucose=5.34 vs. 5.22 mmol/L, p=0.03) despite similarities in obesity and total sugar and calorie availability. These results suggest that countries with higher availability of HFCS have a higher prevalence of type 2 diabetes independent of obesity.

https://doi.org/10.1080/17441692.2012.736257

And yes, much of it is about type 2 diabetes (a major risk factor with COVID-19) but there’s more to the story. Go watch the whole video.

 

 

Friday night delight: Liszt,. Concert Etude #3 in Db major, “Un Sospiro” (a sigh)

[no COVID19 post today — probably tomorrow]

Here are two performances of a little gem among Liszt’s earlier, flashier work. Before Liszt retired from the concert stage, his archival was the now-mostly forgotten Sigismund Thalberg, whose “party trick” was to keep a melody going on top of a two-handed accompaniment. Liszt was dismissive of what he might have called a “gimmick” of he spoke English, but he then exploited it to great effect in some of his own compositions, notably the famous “Liebestraum” in Ab major, and the following piece. Enjoy!

 

 

And while I’m at it, let me share a piece in the same key that appears in Operation Flash, Episode 3, where the two protagonists meet, and Diana Slater lacks the words to tell Felix Winter what is on her mind. 

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

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

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

 

 

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

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

 

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

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

 

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

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

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

 

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

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

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

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

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

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

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

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

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

 

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

 

 

COVID19 update, June 10, 2020: Interview with Norwegian public health chief; tug-of-war over testing in Israel; COVID-19 outbreak on Dutch mink farms

Some quick updates after a long, busy workday.

(1) UnHerd interviews Norway’s public health chief, Camilla Stoltenberg. [Her brother is NATO Sec.Gen., father was FM of Norway]. 

At 7:30 into the video. Camilla Stoltenberg says that it was with hindsight unnecessary to close down schools.

Distance: we had 2m until recently, now we updated to 1m because so few people still have the virys

Face masks: Norway has no general mandate, and she sees no adequate reason for one.

It is interesting that she, and her Swedish colleague Anders Tegnell, started out from very different positions and converge at least partly toward each other.

(2) Israel is seeing a second ripple, if not a second wave. Pretty much nobody has the stomach for a second lockdown, so “test, track, trace” is the mantra. Haaretz reports |(h/t: Mrs. Arbel) on the tug-of-war to control the testing effort. In one corner is  the  emergency commission, led by Weizmann Institute professor Eli Waxman, which stresses efficiency and rapid turnaround. In the other corner is the healthcare bureaucracy which appears to fear encroachment on its territory., and as the remedy for its comparatively slow turnaround proposed budget and personnel increases for itself.

Honestly, I am somewhat puzzled why RT-PCR testing somehow must be under the auspices of healthcare bureaucrats when Israel has a solid biotech industry and research academia that has come up with some very creative ideas in the area of high-throughput testing.

(3) Coronavirus rips through Dutch mink farms, triggering culls to prevent human infections, reports the news section of SCIENCE magazine. (A preprint of the paper is at https://doi.org/10.1101/2020.05.18.101493v1 )

The mink outbreaks are “spillover” from the human pandemic—a zoonosis in reverse that has offered scientists in the Netherlands a unique chance to study how the virus jumps between species and burns through large animal populations.

But they’re also a public health problem. Genetic and epidemiological sleuthing has shown that at least two farm workers have caught the virus from mink—the only patients anywhere known to have become infected by animals. SARS-CoV-2 can infect other animals, including cats, dogs, tigers, hamsters, ferrets, and macaques, but there are no known cases of transmission from these species back into the human population.

The first two mink outbreaks were reported on 23 and 25 April at farms holding 12,000 and 7500 animals, respectively. More mink were dying than usual, and some had nasal discharge or difficulty breathing. In both cases, the virus was introduced by a farm worker who had COVID-19. Today, it has struck 12 of about 130 Dutch mink farms. Once COVID-19 reaches a farm, the virus appears to spread like wildfire, even though the animals are housed in separate cages. Scientists suspect it moves via infectious droplets, on feed or bedding, or in dust containing fecal matter.

That mink are susceptible wasn’t a surprise, because they are closely related to ferrets, says Wim van der Poel of Wageningen University & Research, which has an animal health laboratory here. (Both mink and ferrets can also contract human influenza viruses.) Like humans, infected mink can show no symptoms, or develop severe problems, including pneumonia. Mortality was negligible at one farm and almost 10% at another. “That’s strange—we don’t really understand it,” says virologist Marion Koopmans of Erasmus Medical Center in Rotterdam. Feral cats roaming the farms—and stealing the mink’s food—were found to be infected as well. 

The Netherlands is the only country so far to have reported SARS-CoV-2 in mink. In Denmark, the world’s largest mink producer, “We have not recorded any similar disease or outbreaks,” says Anne Sofie Hammer, a veterinary scientist at the University of Copenhagen. Neither has China, the second largest producer, says virologist Chen Hualan of the Chinese Academy of Agricultural Sciences. (Hubei, the province hardest hit by COVID-19, does not have mink farms, she notes.)

The Dutch outbreaks are giving scientists a chance to study how the virus adapts as it spreads through a large, dense population. In some other animal viruses, such conditions trigger an evolution toward a more virulent form, because the virus isn’t penalized if it kills a host animal quickly as long as it can easily jump to the next one. (Avian influenza, for instance, usually spreads as a mild disease in wild birds but can become highly pathogenic when it lands in a poultry barn.) Although SARS-CoV-2 is undergoing plenty of mutations as it spreads through mink, its virulence shows no signs of increasing.

Read the whole thing. The article also points out that mink farming, under pressure from animal rights’s groups. will be banned in the Netherlands from 2024 on anyhow, so a number of farmers may decide to throw in the towel early.

(4) How predictable. How transparent. How pathetic.

[NB: I haven’t forgotten about yesterday’s NATURE paper on NPI’s, but want to blog about it when I’m not asleep on my feet.]

 

 

 

COVID19 update, June 9, 2020: Matt Ridley on parallels with the 1890 flu epidemic; 57% infected in Bergamo, Italy; corroboration of different susceptibilities between blood groups

(1) (H/t: masgramondou). Matt Ridley tells the story of the 1890 Russian flu epidemic 

The killer came from the east in winter: fever, cough, sore throat, aching muscles, headache and sometimes death. It spread quickly to all parts of the globe, from city to city, using new transport networks. In many cities, the streets were empty and shops and schools deserted. A million died. The Russian influenza pandemic of 1889-90 may hold clues to what happens next — not least because the latest thinking is that it, too, may have been caused by a new coronavirus.

In addition to the new diseases of S[ARS], M[ERS], and C[COVID]-19, there are four other coronaviruses that infect people. They all cause common colds and are responsible for about one in five such sniffles, the rest being rhinoviruses and adenoviruses. As far as we can tell from their genes, two of these coronaviruses came from African bats (one of them bizarrely via alpacas or camels), and two from Asian rodents, one of the[se] via cattle.

It sounds very  familiar… (Note that at the time, not everybody even believed in bacteria — and the first virus was only discovered eight years later by Martinus Beijerinck.)

Genetic analysis by the Belgian virologist, Prof. Marc van Ranst at the University of Leuven, suggests OC43, one of the four common cold coronaviruses diverged away from a pneumonia virus in cattle around 1890. Matt Ridley describes the hypothesis that OC43 was the pathogen of the 1890 Russian Flu, then gradually evolved away to a much more contagious, but infinitely less harmful, form.

 

 

The first case is thought to have been in Bukhara, in central Asia in the spring of 1889, but by October, Constantinople and St Petersburg were affected. In December, military hospitals in the Russian capital were overcrowded, factories and workshops closed for lack of workers and ‘whole districts of the city were abandoned by the population’, according to one report. The symptoms were said to include headache, fever, aching bones, facial rash and swollen hands. The illness lasted for five or six days but sometimes left the patient exhausted for weeks.

The virus reached Paris in November. By the turn of the year, with hospitals full, patients were housed in military barracks and tents in the city’s parks. […] In Vienna the schools closed early for Christmas and stayed closed till late January. In Berlin, it was reported that many post-office staff were affected. In London so many lawyers fell ill that the courts were closed for a while. One day in January at St Bartholomew’s Hospital in the City of London, Dr Samuel West found more than 1,000 people crowded into the casualty ward, most of them men.[Sounds familiar?] […]

According to a modern analysis, the death rate peaked in the week ending 1 December 1889 in St Petersburg, 22 December in Germany, 5 January 1890 in Paris, and 12 January in the US. [The basic reproductive number] R0 has been estimated at 2.1 and the case fatality rate was somewhere between 0.1 per cent and 0.28 per cent: similar figures to today’s pandemic.

Contemporary newspaper reports say that like today’s epidemic, the Russian flu appeared to attack adults more than children, and in some schools the teachers were all affected but not the pupils. Like today’s virus, it was, intriguingly, reported to affect men much more badly than women. Newspapers were filled with statistics of mortality, anecdotes and reassuring editorials.

By March 1890 the pandemic was fading in most places, just as common colds and flu do in spring today. The seasonal pattern displayed by colds and flus is so striking that it cannot be a coincidence that today’s pandemic was also in retreat by May all around the world, irrespective of the policies in place. By the northern summer of 1890 the virus was ensconced in the southern hemisphere, having reached Australia in March. It returned to Europe the following winter and for several years after.

If OC43 was the cause of the 1889-90 pandemic — far from proven, of course — and given that it is the cause of perhaps one in ten colds today, then it has evolved towards lower virulence. It is easy to see how this occurs with respiratory viruses, which are transmitted by people chatting and shaking hands. Mutations that affect the severity of the virus also tend to have an impact on whether people pass it on: if it sends you to bed feeling rotten, you will not give it to so many people. In the inevitable struggle for survival, the milder strains will gradually displace their nastier ones. This is why so many cold viruses affect us but so few kill us, except maybe when new to our species.

Perhaps, too, a degree of immune response in the population helps moderate the effects of the virus, even if not achieving full and permanent immunity. Some cross–immunity seems to exist today, whereby those who have had coronavirus colds do not catch, or do not suffer severely from, Covid-19.

 

(2) Die Welt reports that in the Italian city of Bergamo (classical music lovers may think of Debussy’s Suite Bergamasque) no fewer than 57% of 10,000 tested subjects had antibodies for COVID19. (This is most definitely in 1st-order ‘herd immunity’ territory.) Among a similar-sized (10,400) sample of healthcare workers, “only” 30% had antibodies (which is in the 2nd-order herd immunity range).

In a summary of the state of the epidemic so far, the German daily quotes virologist Prof. Christian Droste, who in an interview in Der Spiegel states that with our present state of knowledge, it is time to shorten the 2-week quarantine in case of exposure to just one week.

(3) A German-Norwegian collaboration, reports Die Welt, found confirmation of earlier indications that blood groups have an effect on disease progression. A+ are worst off (oh joy ;)), while O imparts a degree of protection.

Dass die Blutgruppe Krankheitsverläufe beeinflussen kann, ist grundsätzlich nichts Neues. So gibt es schon seit Längerem Hinweise darauf, dass Blutgruppe 0 auch vor schweren Malaria-Verläufen schützen kann, dafür aber anfälliger für Magen- und Darminfektionen macht, während Träger der Blutgruppen A, B oder AB besser gegen die Pest gewappnet sind.

[That blood groups can influence disease progression is fundamentally nothing new. There have for long been indications that blood group O can also protect for severe malaria [!!], but makes one more susceptible for gastro-intestinal infections, while carriers of blood groups A, B, or AB are more resistant to the plague.

Preprint: https://www.medrxiv.org/content/10.1101/2020.05.31.20114991v1.full.pdf+html

Laut Blutspendedienst des Bayerischen Roten Kreuzes haben 37 Prozent der Bevölkerung die Blutgruppe A Rhesus Positiv und 35 Prozent die Blutgruppe 0 Rhesus Positiv.

[According to the blood donation service of the Bavarian Red Cross, 37% of the [German] population have blood group A+ and 35% O+.]

(4) A new Nature paper “Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe”

http://doi.org/10.1038/s41586-020-2405-7

(This is a “postprint”, i.e., accepted version after peer review, but without copy-editing by the publishers and corrections in proof.) I will probably devote tomorrow’s edition to discussing this paper. (The hoary sketch comes to mind: “Why are you spraying pesticides on an organic garden?” 

“Those aren’t pesticides, that’s a powder against elephants.”

“But there aren’t any bleeding elephants here!”

“Yeah, good stuff, huh?”)

 

(5) Apropos of nothing:

“Liberty is for science what air is for an animal: when deprived of liberty, [science] dies of suffocation as surely as a bird deprived of oxygen. […]

Thought must never submit —

neither to dogma,

nor to party,

nor to passion,

nor to special interest,

nor to a preconceived idea,

nor to anything but the facts themselves —

for when thought submits,

that means it ceases to be.”

—Henri Poincaré, Le libre examen en matière scientifique (1909)

COVID19 update, June 8, 2020: timeline pushed back to October 2019?; leaked German Interior Ministry internal report; hydroxychloroquine prophylactic use study

Just a few quick updates today, as things were busy at work.

(1) The time line for the epidemic keeps getting pushed back further? According to an ABC exclusive report , satellite imagery of parking lots of Wuhan hospitals in October 2019, compared to the same month the previous year, indicate unusual levels of activity. Moreover, internet searches on Baidu at the time supposedly had a number of queries for flu/SARS like symptoms. I am not wholly convinced, but who knows?

 

(2) An internal German report from “Referat KM4” of the BMI (Federal Interior Ministry), that was strongly critical of the “overreaction” of the German government to the pandemic, was leaked to the press. A PDF of the full text is here: (accompanying provenance info): Powerline has a summary in English. A little googling turned up an organigram in which KM4 shows up as “Schutz kritischer Infrastrukturen” (protection of critical infrastructures), one of six Referate (idiomatically: desks, sub-departments) in the department Krisenmanagement und Bevolkungsschutz (Crisis Management and Population Protection).

The report argues that mortality is a small fraction of the annual all-cause mortality in Germany [of course, this argument is open to the “well, that is so because we took action quickly” argument], and indeed, worldwide excess mortality at the time of writing (May 11) was one-sixth of that during the 2017/8 seasonal flu epidemic.

I haven’t waded through the entire report, which is nearly 100 pages long, but it is preceded by a 2-page Kurzfassung (“short version”, idiomatically “Executive Summary”). Item 3 of the Executive Summary speaks of a “Fehlalarm” (false alarm) and laments:  

The fact that the suspected false alarm remained undetected for weeks has a major reason
that the existing framework for action of the crisis unit and the
crisis management in a pandemic do not include appropriate detection tools that
automatically trigger an alarm and initiate the immediate cancellation of measures
as soon as either a pandemic warning turned out to be a false alarm or
it is foreseeable that collateral damage — particularly in terms of destruction of human lives — threatens to become larger than the health consequences and especially the lethal potential of the disease under consideration.

The report explicitly distances itself from economic cost-benefit calculations and, in item 4, argues that collateral damage in lives is larger than the damage of the original epidemic. 

Probably the most inflammatory sentence of the executive summary is “One reproach [from the public] might be that, in the Corona crisis, the State has shown itself to be one of the greatest producers of fake news” (Ein Vorwurf könnte lauten: Der Staat hat sich in der Coronakrise als einer der größten fake-news-Produzenten erwiesen.)”

German governmental authorities have tried to dismiss this report as “one person’s opinion”, but — agree with the report or not — it seems to be a good deal more than that. 

(3) Dr. Seheult looks at another hydroxychloroquine clinical trial: this time it looks at a prophylactic regime.

https://doi.org/10.1056/NEJMoa2016638

A group of about 800 patients who reported high-risk contact (nearer than 6th for more than 10 minutes) with a known COVID-19 carrier was split into two arms. One arm was given a 5-day hydroxychloroquine (HOcq) regimen, the other a placebo. Interestingly, and noted by Dr. Seheult, again no zinc!

The percentage of people who developed COVID19 was somewhat lower in the HOcq arm (11.8%) than in the placebo arm (14.3%), but with this sample size, there is about one chance in three the difference is due to chance. (What he didn’t highlight is that, even with high-risk contacts, the risk of contagion is much lower than you might intuitively expect.) 

A fairly large proportion of test subjects in the HOcq arm reported gastrointestinal complaints, but interestingly, no severe adverse events were reported. (HOcq is known to lead to QT-prolongation: in combination with other drugs that do this, such as the macrolide antibiotic azithromycin, the cumulative effect may lead to heart arrhythmias.)

Anyway, let Dr. Seheult explain it himself:

 

(4) Dr. Mike Hansen discusses differences between autopsy reports of COVID19 deaths and deaths from seasonal flu

COVID19 update, June 7, 2020: Do-it-yourself COVID-19 tests found to be more accurate as well as comfortable; Israeli study confirms protective effect of smoking?!; “half of colleges may close in the next 5-10 years”

(1) Via Instapundit, a popular writeup of a study that found samples acquired by the patients themselves were more accurate than the usual deep nasal and pharyngeal swabs, and not just more comfortable. Besides, they are less likely to expose healthcare personnel, as deep sampling often causes sneezing, coughing, and gagging.

I should perhaps clarify here that the accuracy-limiting factor of RT-PCR testing, at this point, is not the testing apparatus at all (with lab-prepared samples, accuracy approaches 100%) but the sampling technique.

 

The original scientific article about the study was published in the New England Journal of Medicine: http://doi.org/10.1056/NEJMc2016321

Here is an animation of how, once the sample has been acquired, RT-PCR testing works in the lab.

 

(2) There were several reports that, counterintuitively, smokers were underrepresented among COVID19 positive cases. Now in https://www.medrxiv.org/content/10.1101/2020.06.01.20118877v2.full.pdf is an intriguing large-sample study from doctors associated with Clalit Health Services, the largest HMO in Israel which has about 3 million patients in its central database. [Full disclosure: we are insured through a competitor. All four authorized HMOs operate such databases—unlike with Surgiscape, I have every reason to believe these data are kosher.]

As of the cutoff date (May 16), over 145,000 adults insured with Clalit underwent RT-PCR testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),  3.3% of which tested positive. After discarding cases aged under 18 and over 95, as well as those where it was unknown whether they smoked or not, the authors were left with 4,235 positive tests and 124,192 negative. Out of the latter, they randomly selected a control sample of 20,755 patients (5x as many) that matched statistical make-up of the positive sample in terms of gender, age distribution, and ethnosocial group — Jewish Orthodox, Arab, General(mostly Jewish non-Orthodox).

Guess what: Statistically, 9.8% of the  COVID19 positive cases smoke currently, one-half the percentage in the control group 18.2%. Because of the large sample size, p<0.001, i.e., the probability that this result could have arisen from “the luck of the draw” is less than 0.1%. There was no significant difference for past smokers (11.6 vs. 12.9%) — it’s definitely got something to do with current smokers (nicotine or some other component of tobacco smoke).

Of the COVID19-positive tests, 1.8% deceased, 2.0% hospitalized in severe condition, 4.0% in moderate condition, 15.0% in mild condition, the remaining 77.2% did not require hospitalization. There was no significant correlation between the degree of severity and the patient’s smoking status.

Changeux et al11, relying on similar observations, propose a crucial role for the nicotinic acetylcholine receptor (nAChR) in COVID-19 pathology. According to their neurotropic hypothesis, SARS-CoV-2 invades the central nervous system through the nAChR receptor, present in neurons of the olfactory system, as reflected by the frequent occurrence of neurologic symptoms, such as loss of smell or taste, or intense fatigue in patients affected by COVID-19. Other mechanisms may also affect SARS-CoV-2 infection potential in smokers. It is widely accepted that the angiotensin converting enzyme 2 (ACE2) represents the main receptor molecule for SARS-CoV-2, and smoking has been shown to differentially affect ACE2 expression in tissues12–14. Other putative explanations could involve altered cytokine expression such as IL-6, for which increased levels are associated with unfavorable disease outcome14,15.

 

 

(3) Business school professor admits that as many as half of tier-2 colleges will be gone in the next 5-10 years. This was a bubble waiting to burst anyway: the COVID-19 crisis and the attendant shift to online learning is just precipitating the burst, the way Amazon and online shopping more generally were the downfall of many a brick-and-mortar store.

(4) This is the sort of behavior that makes me cringe in embarrassment for my profession. True scientists follow the facts wherever they lead, and seek the truth wherever it may be found. Political hacks exist in every profession — but they are especially grating in ours. And when the public loses all faith in us because of such politicized hacks, it will be blamed on “anti-science” and anti-intellectualism.