COVID19 update, May 31, 2020: which patients benefit most from Remdesivir; asymptomatic infection rate; the post-lockdown economy; miscellaneous updates

(1) Dr. Seheult discusses remdesivir for different categories of patients, and suggests that the drug is most beneficial (in terms of quicker recovery) for patients sick enough to require oxygen, but not so sick as to require mechanical ventilation or ECMOs (“heart-lung machines”). In this latter group, the virus has already done so much damage that remdesivir amounts to “closing the barn door after the horses have fled”, while mild cases will resolve on their own.

The conventional division of patients is (averaged across age groups):

• 80% self-limiting, self-resolving disease
• 15% get more severely ill
• 5% critically ill

So it would be the 15% where the drug can make most of the difference, probably by keeping patients from moving into the 5% critical group. 

(2) Dr. John Campbell’s video looks at the asymptomatic infection rate, which he frustratingly places “between 5% and 80%”, and briefly highlights different studies that arrive at wildly different rates. My working assumption all along has been “about 50%”. 

(3) The Economist has a somewhat pessimistic take on the post-lockdown economy. Note that at least some of the economic effects of the pandemic are also felt in countries that never locked down, like Sweden.

Relatedly, Die Welt (in German) looks at how in reopened Germany, spending habits have changed to the extent that some retailers say they don’t see the point of reopening. The main shopping streets have seen foot traffic dwindle by 30 to 75% (Berlin’s famous Kurfürstendamm was hardest hit). Stores with an online presence, who kept in touch with customers during the crisis, have weathered the storm better, while some with a primarily online business model have seen revenue rise (including a new online grocery shopping chain).

(3) Miscellaneous updates:

Moderna’s COVID-19 vaccines now moves into Phase 2 clinical trials, reports the Jerusalem Post, who also note that the chief scientific officer of Moderna is an expat Israeli. (Like in information technology, tiny Israel punches well above its weight in biotech.)

Forbes highlights what it calls the most important COVID-19 statistic: 42% of US deaths occur in a group that is just 0.6% pf the US population, namely care home residents.

Oddly enough: Monkeys steal COVID-19 testing samples in India. 

Tangentially related, the Daily Telegraph looks at what awaits Hong Kong under full ChiCom rule. The UK has offered asylum to Hong Kongers who still hold BNO (British National Overseas) passports. (This unusual type of passport does not come with automatic “right of abode” in the UK.)

COVID19 update, May 30, 2020: Fang Fang’s “Wuhan Diary”

The Chinese novelist Fang Fang has lived most of her life in Wuhan, going back to the days before the Cultural Revolution. Until her retirement, she used to be the provincial chair of the Chinese Writers Association. 

(Wuhan, the capital of Hubei province, was originally three separate cities named Wuchang, Hankou and Hanyang, all lying on the confluence of the Han and Yangtze rivers.)

When it became clear that an epidemic was breaking out, she started writing diary entries and posting them  on Chinese social media. They quickly acquired a following in the millions, despite furious attempts of online censors to airbrush them away. By the time the lockdowns on Wuhan were lifted, the combined diary had reached book length.  

Now translations in both English and German have come out. I read the English translation, which is available on Amazon. The rating is dragged down by a number of 1-star reviews posted by obvious “50-Cent Army” troll reviewers. So I decided to read the book for myself.

I warmly recommend it, despite its high price ($19.99). It is a unique first-person document by an articulate person with lots of contacts, including in the medical system.

It seems that the Wuhan residents were just as bamboozled by the ChiCom regime as the West. Doctors at the Central Hospital apparently realized early on that they were not just dealing with a new SARS-like infection, but that it was contagious person-to-person. After attempted whistleblower  Dr. Li Wenliang was strong-armed by the police into confessing he had been spreading false news, the others apparently restricted themselves to quietly warning each other. Yet officials eventually realized something was up and organized a high-level meeting on the 14th, which ended inconclusively. Even the Chinese New Year celebration was allowed to proceed.

She tells numerous stories of friends, acquaintances, and relatives who succumbed to the disease — many of them surprisingly young. Many medical personnel (including Li Wenliang) were among the early casualties, but also such people as journalists and cameramen.

She also relates the harrowing period where the local medical system was overwhelmed and patients would die while waiting to be admitted. This was a brief situation, alleviated when medical personnel and supplies started flowing in from other parts of China. 

She highlights the inventiveness of the locals in coping with the lockdowns and the attendant logistical problems. For example, as trying to shop individually was problematic (you were allowed out of your apartment complex once every 3 days) and often stores could not handle the flood of calls, an informal association of residents would collect orders, place a centralized bulk order, then distribute the ordered grocery parcels, at first by placing them in the building’s courtyard, then by placing them in buckets lowered from the windows of residents.

Food donations from other parts of China were apparently abundant enough that distributing them before they spoiled became a problem. She proposed a surprisingly (or not) “capitalist” solution: deliver to grocery stores (who have the storage and the delivery network in place), and let them resell at highly discounted prices meant to cover their distribution costs. 

While she affirmed the necessity of a strict lockdown, she highlights a number of instances where unthinking and callous enforcement of the letter of regulations, with no room for common sense, led to suffering and deaths. (One example that stands out in my mind was a special-needs child left to fend for itself when its father was placed in isolation. Another was a married couple stuck on a bridge between two boroughs because the two spouses had residence permits for opposite banks of the river.) 

“People often have reasons that they use to describe their actions, such as “we were just carrying out written directives.” But reality is filled with all kinds of unpredictable changes, whereas written directives are often prepared hastily with only broad guidelines. Moreover, those written directives are mostly composed with common sense in mind, so they are usually not in direct contradiction with the basic principles of humanitarianism. All we need is for the people assigned to enforce these principles to have just a little more humanistic spirit; just enough so that a driver who had been stuck out on the highways for more than 20 days wouldn’t end up with his life in danger; just enough so that when someone is infected with coronavirus, a crowd of people doesn’t end up sealing their front door with a steel rod so that everyone is locked inside; just enough so that when an adult is forced into mandatory quarantine, their children don’t end up starving to death alone at home. That is all I am asking for.”

Some of her tales will sound familiar — for example, how the suspension of all non-emergency medical services at the height of the epidemic led to other medical problems being neglected (e.g., dialysis and chemotherapy cases). (Apparently she and two of her siblings are diabetic, and the siblings have additional chronic medical problems, so this is something they experienced first-hand. Her ex-husband caught COVID but survived.) 

She also described, via her medical contacts, that mortality at the hospitals decreased once the capacity crunch was over and the doctors had refined their treatment protocols. She mentions remdesivir being applied with some success: non-intubated patients were also often treated with traditional Chinese remedies alongside Western medicine. She herself took various herbal potions in an attempt to boost her immune system. 

Telling it like it is, warts and all, earned her enemies, and even death threats.

“Today there is something I want to get off my chest that has been weighing on me for a long time: Those ultra-leftists in China are responsible for causing irreparable harm to the nation and the people. All they want to do is return to the good old days of the Cultural Revolution and reverse all the Reform Era policies. Anyone with an opinion that differs from their own is regarded as their enemy. They behave like a pack of thugs, attacking anyone who fails to cooperate with them, launching wave after wave of attacks. They spray the world with their violent, hate-filled language and often resort to even more despicable tactics, so base that it almost defies understanding.”

In a footnote, she explains that by ultra-leftists she means ultra-Maoist nostalgics for the Cultural Revolution era, opposed to the reformist polices introduced by Deng Xiaoping.  These people report her posts on the Chinese Twitter-clone and managed to get her account blocked a number of times.

In this atmosphere, newspapers practice self-censorship. She highlights the story of a man who left a testament of 11 word, “I donate my body to the state… what about my wife?” where the newspaper would only highlight the first seven words as concern for his surviving spouse was apparently not worthy of sharing the limelight with his selfless devotion to the state.

(She does mention that autopsies of people like that man were invaluable in helping doctors understand what they were dealing with, notably the ARDS.)

The party leadership and officialdom — well, let me quote her:

“The world of officialdom is filled with people who have never learned a damn thing in their entire lives, but one thing they have mastered is the art of putting on a show; and they have ways to deal with you that you would have never imagined even existed. Their ability to shirk responsibility is also second to none; if they didn’t have a good foundation in all these worthless skills, this outbreak would have never grown into the large-scale calamity that it is today.”

She mentions that three groups of specialists had come to visit during the earlier stages of the outbreak. The first two had accepted the claim that no person-to-person transmission took place, but the leader of the 3rd group —  one Dr. Zhong Nanshan, who had earned his spurs in managing the original SARS outbreak — did not take no for an answer. Under insistent questioning, it was admitted that a patient had infected 14 others, and he announced on January 20 that person-to-person transmission did take place. By then, of course, precious time had been lost.

 

 

 

 

COVID19 update, Shavuot edition: Singapore research finds 50% of sample has pre-existing immunity

Breaking news (via Instapundit): Prof. Francois Balloux from UCLondon highlights preprint from Singapore: https://doi.org/10.1101/2020.05.26.115832

Recent preprint reporting that 24/24 (100%) people form Singapore infected by SARS-1 in 2003 have pre-existing T-cell immunity against #SARSCoV2, but more surprisingly 9/18 (50%) with no exposure to SARS-1 also possess T-cells targeting #SARSCoV2.

One take[-]home message is that infection with coronaviruses induces strong and long-lasting T-cell (cross-)immunity. T-cell immunity is likely a far more important for our immune response to #SARSCoV2 infection than antibodies, in line with other recent reports.

What remains unresolved is which virus caused T-cell immunity in the people with no prior exposure to SARS-1 in 2003. We know of seven coronaviruses infecting humans: #SARSCoV2, SARS-1, MERS and four causing ‘common colds’ (OC43, HKU1, 229E and NL63). [NB: most common colds are caused by rhinoviruses, which are a different family]

Intriguingly, none of the known viruses in circulation in humans looks like a good candidate for the T-cell immunity to #SARSCoV2 in those with no prior exposure to SARS-1. This might suggest that other yet unknown coronaviruses could have been in circulation in humans.

No surprise that having had SARS 1.0 would protect you against SARS 2.0, but nice to know. But that half of a random sample would have immunity owing to previous exposure to a common cold-level virus… If confirmed on a larger sample, this could be yuge. Put this together with the 2nd-order correction for the herd immunity threshold, and acquiring herd immunity could take a lot less doing than previously assumed…

Developing…

Happy Shavuot to my fellow Jews!

UPDATE 1: Dr. Anthony Fauci no longer considers 2nd wave inevitable.

“We don’t have to accept that as an inevitability. Particularly[…] when people start thinking about the fall. I want people to really appreciate that, it could happen, but it is not inevitable.”

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 27, 2020: Norwegian official report now questions necessity of lockdown; Dr. John Campbell on The Lancet hydroxychloroquine study

 

(1)  According to the Spectator (UK), a report (in Norwegian) by the Norwegian public health authority now argues their lockdown was probably unnecessary as voluntary social distancing efforts were already effective enough.

Norway is assembling a picture of what happened before lockdown using observed data – hospital figures, infection numbers and so on – to assess the situation in the country in March. At the time, no one really knew. It was feared that Covid was rampant with each person infecting two or three others – and only lockdown could stop this exponential growth by cutting the R number to 1 or lower. But the country’s public health authority has published a report with a striking conclusion: the virus was never spreading as fast as had been feared and was already on the way out when lockdown was ordered. ‘It looks as if the effective reproduction rate had already dropped to around 1.1 when the most comprehensive measures were implemented on 12 March, and it would not take much to push it down below 1… We have seen in retrospect that the infection was on its way out.’

This raises an awkward question: was lockdown necessary? Could voluntary social distancing alone have achieved the same outcome? Camilla Stoltenberg, director of Norway’s public health agency, has given an interview where she is candid about the implications of this discovery. ‘Our assessment now, and I find that there is a broad consensus in relation to the reopening, was that one could probably achieve the same effect – and avoid part of the unfortunate repercussions – by not closing. But, instead, staying open with precautions to stop the spread.’ This is important to admit, she says, because if infection levels rise again – or a second wave hits in the winter – you need to be brutally honest about whether lockdown proved effective.

Norway’s statistics agency was also the first in the world to calculate the permanent damage inflicted by school closures: every week of classroom education denied to students, it found, stymies life chances and permanently lowers earnings potential. So a country should only enforce this draconian measure if it is sure that the academic foundation for lockdown was sound. And in Stoltenberg’s opinion, ‘the academic foundation was not good enough’ for lockdown this time. The leading article in the new Spectator, out tomorrow, argues that Britons deserve the same candour.

I don’t have enough Norwegian to read the entire report: I will try to get a contact there to help me out. A member of our own ad hoc commission described the situation around the time as “fog of war” (ar`afel krav) — I can understand that, with incomplete information, the Norwegians made the decision they did. (They also had more economic ‘buffer capacity’, as it were, to absorb the economic blow than many others. Their mortality statistics are just 235 dead out of a population of 5.3 million.) 

I would like to venture, however, that “to lockdown” or “to go Swedish”  is a false binary choice. Norway is a very large country with vast differences in population density: I see no intrinsic reason why greater Oslo, for example (and perhaps Bergen and Trondheim) could not have been subjected to a lockdown separately from a more laissez-faire approach for the rest of the country.

Norway started reopening shortly after us — and no, the sky hasn’t fallen there. (We ourselves reopened cafés and sit-down service in restaurants  today, pretty much everything else already being open.)

(2) Dr. John Campbell discusses hydroxychloroquine, the initial encouraging results from clinical trials, and then finally the recent multinational registry analysis published in The Lancet

https://doi.org/10.1016/S0140-6736(20)31180-6

that indicates hospital survival rates are actually lower on HCQ or CQ than without, and that the gap increases when a macrolide antibiotic such as azithromycin is added (presumably owing to heart arrhythmias). Dr. Campbell is clear that neither this study (nor the earlier ones) include zinc supplementation, which would seem to be a fatal flaw.

Collateral results from this very large sample are confirmations of statistical correlation between severity of  COVID19 and factors such as obesity, recent smoking, diabetes, being male, hypertension,… and black or Hispanic ancestry (he again stresses increased propensity for vitamin D deficiency). More surprising was the finding that East Asians (i.e, Chinese, Japanese, and Koreans) appear to be less vulnerable than Caucasians. Taking ACE inhibitors (but not angiotensin receptor blockers) also appears to be correlated with reduced severity, as is taking statins.

(3) For what it’s worth, the CDC website has an aggregator page of the various COVID19 epidemic models. “All models are wrong, but some are useful” (George E. P. Box FRS) — the useful ones now may be those that fit their parameters to the observed time evolution of data.

And while only tangentially COVID19 related, the Jerusalem Post reports on the controversy regarding the tender for building “the largest desalination plaint in the world” Sorek-2 in Israel. The Chinese were poised to win the tender, but following US pressure applied during SecState Mike Pompeo’s visit, an Israeli consortium won out instead. 

 

ADDENDUM: Via commenter “No More Obamas” on Instapundit , here is an article in the Sydney Morning Herald on the Australian lockdown decision 

Australia’s policymakers were in March bracing for up to 150,000 deaths from the coronavirus pandemic as the virus spread globally and health officials warned that hospitals might not be able to cope.

Ten weeks later, with just 103 COVID-19 deaths, some experts say the modelling behind the national cabinet’s decisions was flawed and some commentators say the response went too far.

[…] On Tuesday Chief Medical Officer Brendan Murphy told the Senate inquiry into the Morrison government’s response to the pandemic that Australia had avoided 14,000 deaths by implementing strict social distancing measures, considerably fewer than the initial warning.

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 24, 2020: vaccine trails hampered by dwindling infections; phases in clinical trials; miscellaneous updates

(1) The Daily Telegraph reports that the Oxford/AstraZeneca vaccine trial is now running into an unexpected snag.

At present a Phase 2 trial is underway with 10,000 volunteers, half of whom get the vaccine, the other half a placebo. The idea is to compare the infection rates between the two groups in order to find out whether the vaccine does indeed have protective value.

But currently infections in the UK are falling to the point that simply not enough people may get infected to be able to learn anything from the trial.

(As related here previously, an earlier vaccine for the original SARS, developed by Janssen Pharmaceutica, was never taken into production because the epidemic died out before human trials could be completed.)

According to the Telegraph, three Chinese groups are running into a similar problem with their respective vaccine candidates.

A “plan B” that nobody dares to suggest would be a “challenge trial”. Here, a smaller group of volunteers would agree to be deliberately infected with the virus 2-3 weeks after vaccination. (Here a placebo control group would presumably be unnecessary.) Healthcare workers dealing with COVID19 patients would be another option for a challenge trial, as these would already run plenty of risk of infection. (The cynical mind wonders about recruiting volunteers for a challenge trial among the ChiCom regime fanboys one encounters in academia and the media.)

The Telegraph also addresses earlier reports that rhesus monkeys subjected to a similar challenge trial did shed viral particles from their nose at similar rates as unvaccinated monkeys. Lead developer, Prof. Adrian Hill, however waves this away, as “the monkeys had been deliberately “overdosed” on coronavirus in order to test for safety.”

“We used a really high dose and these guys gave it not just into the lungs and the nose. They gave it into the mouth, and they gave it into the eyes. They gave a huge dose. I mean, seriously, it’s that level of basic.”

UPDATE: Dr. John Campbell on recent vaccine trials

(2) What’s the deal with “Phases” in clinical trials actually? According to ClinicalTrials.gov definitions are as follows

* Phase 0 (a.k.a. Early Phase 1): exploratory trials with microbuses to investigate how or whether a drug interacts with the body.

* Phase 1: safety testing. “They are usually conducted with healthy volunteers, and the goal is to determine the drug’s most frequent and serious adverse events and, often, how the drug is broken down and excreted by the body. These trials usually involve a small number of participants.”

* Phase 2: effectiveness testing. The drug is tested on people who have the condition/disease that it is meant to cure or mitigate. There is almost always a control arm comparable in size and composition: patients in the control arm may receive either a placebo or (where there is one) the current “drug of choice’. Any adverse effects are monitored.

If the drug is found to have a statistically significant ‘therapeutic advantage’, then testing proceeds to 

* Phase 3: “A phase of research to describe clinical trials that gather more information about a drug’s safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. These studies typically involve more participants.”

If the drug passes that stage and gets approved by the FDA and/or its foreign counterparts, it goes to market. Any post-approval studies may be labeled Phase 4.

What if you have an unproven drug that might save a dying patient’s life, and no better option is available? Then a ‘compassionate use exemption’ applies, provided the patient, a licensed physician, and the drug manufacturer are all willing to try this ‘Hail Mary pass’, since the patient is otherwise doomed anyway. A treatment protocol is to be submitted to the FDA. A less formal version is how our first COVID19 cure (“patient #19”) with remdesivir came about.

Now when testing a drug, elaborate and costly as it may be, at least you have a population of patients already sick. With a vaccine candidate you have additional complications.

* You give vaccines to lots of healthy people, and the first rule of the Hippocratic oath (or its Jewish counterpart, the Oath of Assaf the Physician) is primum non nocere/above all, do no harm. 

* Normally, unless (see above) a challenge trial is set up, only a smaller or larger minority of vaccinated people will be exposed to the pathogen. That means that the sample sizes for phase 2 and 3 clinical trials need to be much larger than for a drug.

(3) Some links, you decide

* via David Bernstein, a piece in the Salt Lake Tribune (archive copy here, especially as the SLTrib is not accessible in Europe ) about some probable and unlikely infection scenario’s.  

* Michael Levitt, 2013 Nobel laureate in Chemistry, in an interview in the Daily Telegraph argues that lockdowns did not result in net saved lives and may indeed have had a net cost. I think he oversells his case, but let the man have his say and make up your own mind. https://www.telegraph.co.uk/news/2020/05/23/lockdown-saved-no-lives-may-have-cost-nobel-prize-winner-believes/

* an anecdotal data point: a woman who has been taking hydroxychloroquine for 19 years to mitigate her lupus now contracted COVID19 regardless, and predictably blames…

* hat-tip to Lissa Halley, a study tracing 455 contacts of an asymptomatic carrier (who was hospitalized for an unrelated chronic heart issue) revealed no infections among any contacts. I would like to see further confirmation, as zero infections out of 455 sounds almost too good to be true.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219423/

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

COVID19 update, May 18, 2020: preliminary human vaccine trial results; new BCG study rules out COVID protective effect; the Swedish road alone; more YouTube censorship

Been a crazy-busy day at work, so a few quick updates:

(1) Derek Lowe at Corante reports on the first preliminary results of human trials of the Moderna vaccine. At this point, healthy volunteers were injected with three different doses of the vaccine: 25 µg, 100 µg, and 250 µg. The goal was both to see if antibodies developed (they did, even at the lowest dose) and to establish a safe dosage range. At the highest dose, three volunteers had significant adverse reactions, so that will be off the menu for further testing.

Also from Derek Lowe (hat tip, “Laura R.”) some good news on the human immune response to SARS-nCoV-2.

(2) Miscellaneous updates:

• Israeli doctors report that patients who recovered after being on ventilators for extended periods of time face a long, uphill battle to rehabilitation. (H/t: Mrs. Arbel) Aside from lung muscle atrophy due to being artificially “respirated” for so long, permanent lung tissue scarring often results. At this point, we have fewer than 50 patients on artificial respiration (the Ministry of Health statistics do not distinguish between invasive ventilators and noninvasive respirators). Here are three articles in JAMA (Journal of the American Medical Association) on prone positioning and other noninvasive techniques: one, two, and three.

• Mark Feldman, CEO of Ziontours, looks at the post-COVID19 travel landscape, . Note that this is one sector of our economy that would have taken the same pummeling with or without lockdown.
• An earlier hypothesis that BCG tuberculosis vaccination in childhood might confer some immunity against COVID-19 seems to be refuted by a study from Tel-Aviv U. The original research paper article can be read in JAMA.
• In an article entitled (in German) The isolated Swedish patient, Die Welt once again the Swedish Sonderweg (“special road”). Swedish officials extrapolate that about 30% of the population of Stockholm has antibodies — still some distance to herd immunity in the usual first-order model. [In the second-order “differential susceptibility” model, apparently 30% is already ‘getting there’.] Mortality per 100,000 is much higher than the other Scandinavian countries (see graph below): to be fair, however, there’s another big wave coming in the winter, Sweden may pay the ferryman less then than the other countries.

(3) Via Instapundit, YouTube again covers itself in free speech “glory” (sarcasm tag needed)? An epidemiologist who used to be head of Rockefeller U.’s department of epidemiology and biostatistic is the latest to be declared “doubleplusungood” — essentially for stridently advocating the Swedish model as an alternative to lockdowns. I vehemently disagree with him, but why not debate him in the marketplace of ideas rather than place him on the Index Librorum Prohibitorum?

(4) Instapundit’s feed is full of examples of further protracted lockdown measures being openly defied even in Manhattan (!). He calls this “Irish democracy”. I believe, and continue to believe, that short and intense lockdowns work in densely populated countries like my own — but what is currently going on in some US states amounts to perpetual moving of goalposts, and increasingly looks like a flag of convenience for agendas unrelated to epidemiology. The “Irish democracy” response then sooner or later became inevitable. As I have pointed out earlier, the active cases graphs in European countries (+Israel) that have reopened have yet to show any signs of resurgence.

(5) Finally, as a long-time admirer of Richard Fernandez’s work, I was rather amused to see him use the Cytokine Storm metaphor for blunt-instrument lockdowns that you might have seen here.

COVID19 update, May 17, 2020: Exposé on decision making timeline in Germany; YouTube censorship asininity of the day

(1) DIE WELT AM SONTAG, the Sunday supplement of the German daily, has a very long article detailing the timeline of Germany’s response to the pandemic. I will try to put up a translation somewhere, but the bottom line is: decision makers — both in the government and in the Robert Koch Institute (RKI), Germany’s infectious diseases authority — were lulled into a false sense of security by the misinformation spread by the Chinese regime. The article concludes that if these precious weeks had not been lost, Germany likely would have been able to contain the epidemic without a lockdown, and at a much lower cost in lives (not to mention the ruinous economic cost).

A virologist named Alexander Kekulé [a great-grandson of the Kekulé who first discovered the ring structure of benzene] acted as a Cassandra — saying “this isn’t your garden variety flu, but SARS all over again”— but found little resonance at first. A continuous tension existed between the Minister Jens Spahn and the Interior Minister Horst Seehofer (a former head of the CSU, the Bavarian sister party of Angela Merkel’s CDU). Seehofer favored more restrictive measures than his colleague.

Even as the duplicity and manipulations of the Xi regime became clear, Spahn tried to defend the WHO chief, saying he was in an impossible position since he was wholly dependent on the Chinese for information.

Then a number of things happened in quick succession:

• 100 Germans came in on an evacuation flught from Wuhan. Two tested positive.
• Diamond Princess ship, first major spread outside China
• Examination of the first cases in Bavaria revealed that, unlike the 2002-3 SARS, this virus did not confine itself to the lower lungs but also sat in the throat and upper respiratory system , and therefore could spread much more easily.
• News from Italy came in about the outbreak in the North
• Following carnival celebrations, the first major “community spread” outbreak in Germany
• a German dealer in medical PPE (personal protective equipment) sold out of his entire stock (good for about 5 months of normal sales volume) in a single day, and realized something was up.
• Angela Merkel, in a goodwill gesture, sent 5.5 tons of PPE to China — and in order to do so, had to dig into Germany’s own emergency stockpile, as China was stripping the world market bare
• at an intelligence briefing, the BND (Bundesnachrichtendienst or Federal Intelligence Service, Germany’s CIA) showed satellite footage of mass graves in Iran that indicated the epidemic there was much more severe than they were communicating outside

Once the powers that be finally became convinced they were dealing with a potentially cataclysmic event, Germany appears to have gotten its act together quite rapidly.

(2) A commenter alerted me that Roger Seheult MD’s youtube video about the zinc-hydroxychloroquine combination, which I linked yesterday, had been deleted by YT for “violating community standards”. To call this asinine would be an insult to donkeys. Dr. Seheult is not your garden-variety crank poster pushing quack remedies, but a pulmonologist who actually deals with COVID19 patients and lectures in medical school, and who has been running an excellent medical school tutoring channel named MedCram on YouTube for some time. Whichever self-appointed medical authority at YT decided that we must be protected from “doubleplusungoodthink” ought to be ashamed of themselves.

Let me repeat once again a quote from the French mathematician, theoretical physicist, and pioneering philosopher of science Henri Poincaré that is something of a creed for French (and Belgian) secular humanists, but is a rallying cry for anyone who takes the pursuit of science and truth seriously:

Liberty is for science what air is for an animal: when deprived of liberty, it dies of suffocation like a bird deprived of oxygen. […] Thought must never submit — neither to dogma, nor to party, nor to passion, nor to special interest, nor to preconceptions, nor to anything but the facts themselves — for when thought submits, that means it ceases to be.

Quote from: Henri Poincaré, Le libre examen en matière scientifique [free inquiry in scientific matters], lecture Nov 20, 1909, on the 75th anniversary of the Université Libre de Bruxelles, http://doi.org/10.1007/978-3-0348-8112-8_12

ADDENDUM: Mike Hansen MD on results from autopsies (the paper in the Annals of Internal Medicine being discussed is here: https://www.acpjournals.org/doi/10.7326/M20-2003 )

COVID19 update, May 16, 2020: evidence hydroxychloroquine works better with zinc added; how Taiwan succeeded; Niall Ferguson on his disgraced namesake

(1) When I reported on the failed hydroxychloroquine (HOcq) trial, a number of commenters asked “what about zinc?” It is indeed so that the early reports of success by both Didier Raoult [director of IHU-Méditerranée in Marseille, France] and by Williamsburg, NY community doctor Zev Zelenko included zinc supplementation.
Now the latest video of Roger Seheult MD highlights a retrospective study with zinc+HOcq (plus azithromycin) about which a preprint just was published. And guess what: results there look a good deal more promising if administered early in the disease. That is strongly suggestive of HOcq’s role being that of a zinc ionophore (and, at least in vitro, Zn2+ inhibits with the RdRp, a.k.a. replicase, that copies the viral RNA) https://www.medrxiv.org/conte…/10.1101/2020.05.02.20080036v1  https://www.youtube.com/watch?v=WZq-K1wpur8

(2) Two COVID19-related videos worth watching from the Hoover Institute

(2a) Vice President Chen Chien-jen, Taiwan, himself a reputed epidemiology professor, describes Taiwan’s response, and how they quickly contained the epidemic without lockdowns.

https://www.youtube.com/watch?v=-3Ry6eiKvvw

(2b) Niall Ferguson, the British-born Harvard University historian, discusses the British and American responses to the epidemic, the economic falloutk, and his now-disgraced near-namesake of the “2 million will die” model.

Neil Ferguson (the modeler) reminds me of the Talmudic maxim:

Scholars, be careful with your words, lest you [lead your pupils] to a place of bitter waters, and they drink from it and die — and thus the Name of Heaven will be desecrated.

Pirkei Avot 1:11

ADDENDUM: Quillette has an article from Paulina Neuding, who lives in Stockholm: “Sweden Has Resisted a Lockdown. But That Doesn’t Make it a Bastion of Liberty” [This is aside from issues with its healthcare system reported on earlier.]

In reality, Sweden’s response to the pandemic has less to do with freedom and individual responsibility, and more to do with the country’s tradition of consensus and social control. Its choice of a uniquely lax approach to the pandemic should not be mistaken for a sudden turn toward individual freedom.

The Swedish strategy, devised by a team of government experts headed by chief epidemiologist Anders Tegnell, rests on the assumption that [(a)] COVID-19 cannot be contained, and that [(b)] other international experts are overestimating its fatality rates. Herd immunity is viewed as the inevitable end point, and it is assumed that such immunity can be achieved relatively quickly and at a cost in human lives that will not be too high.

“We have been a bit careful [about] the words [herd immunity] because it can give the impression that you have given up, and that is not at all what this is about… We will not gain control of this in any other way,” Tegnell explained in an interview in March.

[…] Though polls show that most Swedes trust the state consensus, a minority would prefer to have their families self-isolate, but cannot because they risk intervention from social services. Imagine being a Swedish parent who belongs to a high-risk group, and to face the choice between possibly contracting the virus through your child’s school, and that of being reported to the authorities for the offence of homeschooling.

Sweden’s COVID-19 death rate hovers high above that of other Nordic countries, which have chosen a more restrictive strategy. As of this writing, Sweden has 22 deaths per 100,000 citizens—more than five times as many as Norway (four per 100,000) and three times as many as Denmark (seven per 100,000), even though all three countries saw their first fatalities on roughly the same date. But collectivism is deeply ingrained in Swedish culture—for good and ill—and many view it as bad form to question the authorities in the midst of a crisis.

Even though Sweden has taken a path that is extreme compared to virtually all other EU countries, there is limited overt political opposition, and scientists who have criticized the strategy have been victims of vicious attacks on their characters, and are rejected at public events. The rector at a leading Swedish university even saw it necessary to declare in a blog post (available in English) that employees who had publicly criticized the government’s COVID-19 response would not be censored for doing so. That he even saw a need for such a public statement is telling of the current mood in the country.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

COVID19 update, May 14, 2020: drug cocktails greater than the sum of their parts

(1) The term “drug cocktail” is best known from AIDS, where the introduction of “cocktails” of (usually three from at least two different classes) antiretrovirals helped turn HIV from a death sentence into a long-term manageable disease.
Now (h/t: Mrs. Arbel) a team from Hong Kong has achieved excellent results for COVID19 using a different cocktail, reports the Jerusalem Post. The full medical article in The Lancet can be read here: https://doi.org/10.1016/S0140-6736(20)31042-4

The cocktail in question has three components:

• The HIV drug Kaletra, itself a mixture of two protease inhibitors, Lopinavir and Ritonavir.
• The hepatitis drug Ribavirin, a nucleoside analog that can mimic both the letters A and G of the genetic code, and thus messes with copying of the viral RNA (cf. my earlier posts on Remdesivir)
• The immunomodulator Interferon beta-1b, better known to multiple sclerosis patients as REBIF.

The control group was given just Kaletra. Otherwise, both groups received standard supportive care, including antibiotics for secondary bacterial infections.

What’s with the protease inhibitor? Many of these viruses (including SARS-NCoV-2 have their envelope etc. Proteins encoded as a single long “protein sausage” on their RNA. After protein synthesis in the ribosome (the cell organelle that assembles proteins from amino acids according to the ‘program tape’ on the RNA), a protease then splits the ‘sausage’ into individual ‘links’.

So we have two drugs that tamper with the ability of the virus to make its envelope, plus one that inserts junk ‘letters’ in the copied RNA. Even if each partially successful, they will slow down viral reproduction. So what is the role of the beta-interferon? To tell the body’s immune system: “don’t go berserk, take it easy!” and prevent cytokine storm.

If treatment was started less than 7 days after onset of symptoms, the “triple cocktail” group showed better clinical and virological outcomes than the control group across all meaningful measured variables. For the subgroups of patients where treatment was delayed longer, there was no statistically significant difference in outcomes between the cocktail and control group. So early intervention is worth a lot.

Median time to negative RT-PCR test was 7 days for the “cocktail” group, compared to 12 days for the control group.

It’s not a magic bullet drug: every doctor dreams of what Frederick Banting experiences when he first administered insulin to boys in diabetic coma, where the first boys were waking up before he’d finished injecting the last. But that kind of spectacular success is the rare exception in drug research.

What we can safely say we have here, I believe, is a ‘cocktail’ that is greater than the sum of the parts. And a nice thing about cocktails of existing drugs: each component already has undergone clinical trials and obtained FDA (or foreign equivalent) approval individually.

What about side-effects? Reading Table 4 in the paper, the difference with the control group for nausea, diarrhea,… is not statistically significant. No patients in the ‘cocktail’ group suffered severe adverse events, vs. one in the ‘Kaletra only’ control group.

(2) My friend “masgramondou” weighs in on the source code of the “Ferguson Model”: All models are wrong, and some are useless. Or worse than useless, in this case. He points to another model that might at least be somewhat more transparent than the others: https://covid19-scenarios.org, developed by the group of Prof. Richard Neher at U. of Basel, Switzerland.

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