COVID19 update, June 2, 2020: Remdesivir Phase 3 trial results

A short post today, as the day job is keeping me busy. 

 

(1) Today the results of the Phase 3 remdesivir trial were released. (I previously discussed its mechanism of action here: in brief, it’s a nucleoside analog that interferes with viral RNA copying by acting as an “imposter letter” in the RNA genetic code and causing further copying to break off.)

Again, as with prior trials, we see that it’s not a “magic bullet” drug, but clearly has a therapeutic advantage  in patients with moderate disease (signs of pneumonia, but don’t yet need oxygen). The trial used almost 600 patients, divided into three roughly equal groups: (a) standard of care (SOC) + 5-day remdesivir; (b) SOC + 10-day remdesivir; (c) SOC only (control group). In the table below, percentages are given in parentheses:UntitledImage

The “ordinal scale” is an ad hoc 7-point scale ranging from hospital discharge on one end to death on the other end. In the 5-day regimen (which I read between the lines uses twice the dose for half the time), about 10% more patients see an improvement, and 8% fewer patients see a worsening from baseline than with SOC. No patients on the 5-day regime died (compared to four with SOC), but we are in “statistics of small numbers” territory.

As for drug side effects (“AE”), there are about 6% more than with standard care, but actually fewer serious side effects.

Additional Phase 3 trials in severe and moderate disease are in progress in various countries. The drug is currently approved in Japan and under FDA emergency authorization in the US.

 

(2) A few videos:

A 60 Minutes Australia documentary on the Chinese cover-up (see also my earlier post about Fang Fang’s “Wuhan Diary”)

In this video, Dr. Seheult talks about masks and about a database for vaccine clinical trials.

 

 

ADDENDUM: Israeli-developed “disinfection tunnel” sprays harmless disinfectant aerosol generated electrolytically from water and salt

COVID19 update, June 1, 2020: Sweden’s “road alone” and elderly care; avoiding lockdowns in a new flare-up; not even Stanford immune from cuts and layoffs

 

(1) Sweden’s Sonderweg (“special road”, idiomatically, “going its own way”) is the subject of heated debate pro and con.

At first sight, per capita mortality is an order of magnitude higher than in adjacent countries with similar ethnic profile, climate, and sociology. (Sweden does, however, have a higher percentage of 1st-generation immigrants than Norway, Denmark, and Finland — see below.)

At second sight, however, it turned out that Swedish morbidity and especially mortality is disproportionately concentrated in two populations: elderly in care homes (over 70%) and 1st-generation immigrants. Mortality among native Swedes from young to independent elderly, is actually not that elevated compared to the neighbors. 

On the gripping hand, while the Swedes may have avoided the economic ruination of a full lockdown and may be closer to herd immunity now should a second wave arrive, there are costs to this epidemic for everyone (the travel and airline industries, for instance, are on life support everywhere, lockdown or no lockdown). Some aspects of the world economy will be changed forever — and some already existing ‘creative destruction’ trends will be accelerated worldwide. Sweden will see a recession, just not as deep, and possibly with a quicker recovery. 

But let’s come back to those care homes. Die Welt has an exposé on what is going on there: “The true problem of the Swedish sonderweg“. If it were in English, I’d say “read and weep”. But as it’s in German, let me summarize a few points (reader beware):

  • As explained earlier, the Swedish elderly care model is based on encouraging people to live independently for as long as possible, with paid ‘home helpers’ if needed. Assisted living facilities seem to be primarily a private-sector option, while true homes for the elderly are seen as the last resort. Median survival time in them is less than a year
  • Caregivers in these homes were alleged not issued PPEs, and testing was only carried out people who showed symptoms, despite adequate testing capacity being available.
  • The Swedish newspaper Aftonblådet quoted gerontologist Prof. Yngve Gustafsson of Umea University as saying that 70-80% of care home residents admitted to geriatric hospitals with COVID-19 are sent back to the care home. Residents checked into the hospital with COVID19 were often sent back to the home, where of course the infection then spread.
  • He adds that in many cases they don’t die from COVID19 but from secondary infection with bacterial pneumonia, and could be saved with intravenous antibiotics. However, the prescribed care protocol for such patients is purely palliative — Morphin, Midazolam and Haldol – which according to him is a nearly 100% certain death sentence
  • A man named Thomas Andersson, who discovered that his father Jan, aged 81 had been put on this protocol (following diagnosis over the phone!) managed to get the decision reversed after first contacting the care home management, then going to the media. His father was put on an antibiotic IV and, once the bacterial pneumonia receded, managed to fight off the relatively mild COVID19 infection on his own. Below is Jan celebrating his recovery with children and grandchildren. Thomas still cannot believe such a thing was possible in Sweden.

Infuriating and appalling as such stories may be, they have a flip side: that if Sweden hadn’t gone “full Cuomo” on its elderly, its mortality might well have been a fraction of what they have now, and Sweden’s sonderweg might look a good deal better.

(2) Israel is, sadly, seeing a spike in new infections, almost all of them at a few schools in the Jerusalem area. Prof. Eli Waxman of the Weizmann Institute, who led the team that laid out Israel’s COVID19 planning,  discusses here how to handle a possible 2nd wave without lockdowns.

It sounds a lot like what  Norway envisages as its strategy for a second wave: individual test, track and trace as the first line of defense, where speed is of the essence; localized isolation measures as a second line of defense; expanding the ring of those if necessary; but national lockdown only as a very last resort. (It sounds like nobody in Israel, Norway, nor for that matter Belgium has any stomach for a second lockdown. This is especially true as Norway is wondering, with hindsight in numbers, if voluntary social distancing might night have been adequate. Your mileage may vary, of course — Norwegians and Italians, for example, would react very differently to strong social distancing recommendations.)

[…] In Israel, the HaMagen [“The Shield”] app, which was developed and endorsed by the Health Ministry and can tell people if they have been in the presence of anyone who has been diagnosed with coronavirus, could play a key role, he said. “The more people who download it, the better.” 
[In addition, the] Shin Bet [Israel’s domestic security service] was reported to have traced a third of Israel’s coronavirus cases, some 4,089 people, [through their cell phones.  Israel’s Supreme Court has however ruled that this cannot continue past the emergency order, unless anchored in law.]

[…] Waxman said South Korea has two advantages over Israel: It learned the importance of moving fast from its experience with Middle East Respiratory Syndrome (MERS) in 2015, when the virus killed 36 people, infected 186 and put thousands of citizens into isolation. The outbreak was ultimately traced to a single visitor from overseas. 
In addition, South Korea has leveraged some technological tools that “Israel cannot and should not be able to use” because they might infringe on privacy rights, he said.

 

(3) One “industry” which will be hit hard is higher education. Especially in the US, much of it is built upon an unsustainable base, with people paying extortionate tuition for amenities and administrative overhead that has nothing to do with education — be it the country-club level gym and dormitories, the football stadium (which only in a few places is net profitable), or the ever-expanding army of administrators. Now that these places were forced to move to distance learning, they found themselves competing with much cheaper online colleges. Instapundit has endlessly blogged (and written a book) about the “Higher Education Bubble” and the coming wave of creative destruction in that industry: COVID19 only accelerated a process waiting to happen. I had always assumed, however, that blue-chip brandnames like Harvard would be largely insulated. 

Now it turns out that not even Stanford (!) is fully immune, as revealed in a statement by the president

Many of our income streams will continue to be diminished: Housing revenue will be reduced due to fewer students living on campus; income-producing events and programs will continue to be limited; and clinical, research and philanthropic income streams will be challenged. At the same time, expenses in some areas, such as student financial aid, will increase. The market volatility affecting our endowment also can be expected to continue, given the seismic disruptions occurring in the national and global economies.

[…]

We previously asked university units to prepare FY21 budget plans based on a scenario with a 15 percent reduction in funding from endowment payout and a 10 percent reduction in support from general funds. We sincerely hope that the reductions needed will be smaller than this, but for now we need to plan to these targets as a contingency. We expect to provide final allocations of general funds and endowment payout to units by the end of June, enabling them to finalize their budgets in July.

As units plan for budget reductions, we expect there will be reductions in some of the programs each of them is able to offer. We will work to ensure that any program reductions still allow us to sustain Stanford’s core academic strengths and our long-standing commitments to student access.

Given the magnitude of the budget challenge, we also expect that program reductions will make some workforce reductions unavoidable as we enter the new fiscal year. We don’t yet know the scale of job reductions. We hope they will be limited, but they will be driven by the program needs and budget capacity of individual units. Our expectation is that some of these reductions will be temporary layoffs (furloughs) until we are able to resume services and bring employees back, and that other reductions will be permanent layoffs. At this time, we expect to be able to communicate more detailed decisions about layoffs in late July.

It would be too much to hope that the “programs” affected would primarily be silliness such as courses on “the poetics of the lowrider” (as Victor Davis Hanson has described elsewhere), rather than the STEM programs that made Stanford such a powerhouse. But never underestimate the reverse Midas touch of professional college administrators…. 

 

(4) And just because: “June came upon us much too soon…”

 

 

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, 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). […]

 

 

Figure1

(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:

 

ADDENDUM: Mike Hansen MD on vitamin D

 

 

 

COVID19 update, March 21, 2020: Dr. Matt Shelton on vitamin D; Harvard historian Niall Ferguson on how the pandemic exposed the “dysfunctional administrative state”; 2005 CDC paper touting chloroquine for SARS

(1) Dr. Matt Shelton, interviewed by Dr. John Campbell, tells us much more about vitamin D. Amusing statement: “Stay in the sun until you’re halfway to sunburned for your skin type, and you’ve had enough.”

(2) Niall Ferguson, about 10 minutes into this video from the Hoover Institute:

“The pandemic has revealed a terrible pathology at the heart of American political life, and it’s not the one you think. While the media endlessly pore over every utterance of President Trump, the real pathology that the pandemic has exposed is that we have a completely dysfunctional administrative state that is extremely good at generating PowerPoints and multiple-page reports, but when it comes to actually dealing with an emergency, is completely useless.”

Here’s another good one:

(3) My Facebook friend Jeff D. reminds me of a 2005 paper published by a group from CDC in the Virology Journal entitled: “Chloroquine is a potent inhibitor of SARS coronavirus infection and spread”.
http://doi.org/10.1186/1743-422X-2-69

And yes, that’s the old SARS-CoV-1, not the current SARS-nCoV-2 — but some of the people now doing all they can to “prove” HOcq doesn’t work would be quite embarrassed at this article.

(4) Meanwhile, Standard & Poor maintains Israel’s AA- sovereign credit rating, and predicts a “V-shaped recovery“.

Finally, another good one from Unherd: Prof. Karol Sikora, former head of The Who cancer program and Dean of the U. of Buckingham medical school, sounds a largely optimistic note.

 

COVID19 update, May 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.

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.

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”

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 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

COVID19 update, May 11, 2020: hydroxychloroquine bummer; breakthrough in understanding of the severe disease

Two major updates today, one a bummer, one confirmation of an insight at the cellular level.

(1) The first large-scale clinical trial with hydroxychloroquine, at NY Presbyterian, was just published in the New England Journal of Medicine. http://www.nejm.org/doi/10.1056/NEJMoa2012410 Dr. John Campbell comments at length on YouTube, and as is his wont, strenuously avoids politicking. https://www.youtube.com/watch?v=1XCP1WzOY6M

Watch the whole video. But in a nutshell: there is no statistically significant difference in outcomes between the hydroxychloroquine and control arms of the study. This is a major bummer, as many medical professionals (and not just President Trump) had high hopes based on initial positive reports and several plausible mechanisms.

As Dr. Campbell says, it sounded plausible enough at the time they were desperate for something, anything they could repurpose. Especially given the known immunomodulatory effects (cf. use in arthritis, lupus) and as it became increasingly clear people were getting killed by their own immune systems going amok rather than directly by the virus. Besides, it worked in the test tube against the old SARS.

More’s the pity, since it was something they could use off the shelf and didn’t cost an arm and a leg. So far, Remdesivir is the only thing that’s passed the double-blind test [it got FDA approval right after]— and that’s (a) only an incremental therapeutic benefit, no magic bullet; (b) a proprietary drug that Gilead themselves will have to license to other companies because they simply can’t manufacture enough. (Hoffmann-LaRoche probably can.)

(2) Now for the major insight (hat tip: Mrs. Arbel). Haaretz English Edition [*] has a write-up in popular language (archived copy here http://archive.is/g6qaL ) of a paper from the Weizmann Institute that just came out in the prestigious journal CELL. https://doi.org/10.1016/j.cell.2020.05.006

This paper helps rationalize at the level of single cells what has become increasingly clear on an empirical, “macro” level: that COVID19 is really two diseases in one. The first stage is a unpleasant but not life-threatening viral disease — and about 80% of patients on average (fewer for older patients, but over 95% of young patients) just get better on their own, and that’s the end of it. The remainder, who proceed to the second stage, get a massive immune overreaction (“cytokine storm”, CS) that becomes life-threatening (and kills a nontrivial percentage of patients). I have linked the videos by Drs. Hansen and Seheult (both pulmonologists) about the clinical picture in previous updates; postmortem, several German and Swiss pathologists have shared the results of many autopsies. , where severe blood clotting secondary to CS was seen over and over, causing organ failures and strokes as well as ultimately death by heart attack or pulmonary embolism.
Now a paper from the Weizmann Institute, by the team of Prof. Ido Amit at the Department of Immunology, offers a glimpse at what goes on at the cellular level.

In the study, which [also involved] research assistants Amir Giladi and Pierre Bost, researchers used state-of-the-art genomic technologies which included a method known as single-cell genomics, an area developed and led by Prof. Amit. […] By obtaining a picture of the cell at a given moment, one can compare the differences between the activity of cells invaded by the coronavirus in severely and lightly affected individuals. Researchers can see which cells and genes are activated and which cells are silenced, thus learning about changes in inter-cellular communication and about cells that are activated by the virus in areas where it is active.

The key question of what differentiates biological processes and the actions of the immune system in severely ill COVID-19 patients as opposed to those who are slightly ill has been occupying researchers and physicians since the virus was first detected.
In the lungs of seriously ill patients, [Amit and coworkers] found that macrophages – cells that normally assist in ridding the lungs of infection, viruses and microbes – are replaced by cells that exacerbate the illness. The researchers also found that in seriously ill patients, the coronavirus neutralizes the immune system’s T-cells, which also fight infections, thereby allowing other viruses that are present in the body to inflict their damage. […] The researchers behind the study hope that a deeper understanding of the factors leading to a patient’s deterioration will help find weak spots in the chain of reactions initiated by the virus in severe cases, paving the way for effective treatments that would prevent or significantly curtail the impact of the disease.

The pattern of the disease among people who are hit hard is quite clear: After a week of mild symptoms, there is a rapid and sharp deterioration in their condition, characterized by hyperactivity of the immune system called a cytokine storm. This hyperactivity leads to serious damage to a patient’s health, often leading to a collapse of multiple systems, including the heart, liver and kidneys. In the lungs, the disease is characterized by damage to macrophage cells, whose role is to clear the lungs of infections.

The study analyzed hundreds of thousands of cells that were taken from the lung fluid of seriously ill patients, slightly ill patients and healthy people. The researchers discovered which types of cells are invaded by the virus and learned about its pathway. They found that the virus usually attacks epithelial cells, which in the lungs are responsible for respiration by enabling transport of oxygen from the air to the blood. “Due to the infection, the whole immune environment of the lungs undergoes a total transformation” explains Amit.

The study showed that in patients who are severely hit by the virus, there is a dramatic effect on the immune system as compared to patients who are only slightly affected. In the former, macrophages in the lung tissue are replaced by other immune system cells. “We found that they are replaced by monocytes, blood cells which accelerate a cytokine storm. They are recruited from the circulation as part of the overreaction of the immune system,” explains Amit.

The researchers found an enhanced presence of polypeptide cytokines called IL-6 and IL-8 in seriously ill patients. These cytokines are usually released by the monocytes, serving to either augment or suppress inflammation according to need. In this case, they facilitate inflammation. “The cytokine storm produced by the virus prevents the immune system in these patients from launching adaptive processes which are required for mounting an appropriate immune response,” says Amit. “In other studies we’re involved in, together with researchers from China and Italy, we see enhanced cytokine levels in the blood of severely ill patients before any pathological signs are evident.”

Another change that accompanies the cytokine storm involves the activity of T-cells. “In contrast to patients with light symptoms, seriously ill patients have T-cells that are neutralized and inactive,” says Amit. The researchers found that this dramatic change causes indirect damage, such as infection by other viruses which the immune system had previously managed to repulse.

I’d been wondering for a while for how many people who died of COVID19, secondary opportunistic infections (by viruses or drug-resistant “hospital bacteria”) were the proximate cause of death, or a contributory one, even if the root cause was still COVID19.

The researchers are now developing clinical studies that will use treatments to protect macrophages, with the hope that they will be able to prevent a deterioration in patients who are mildly impacted by the virus.

More than that: this may give another impetus to treatments that combine immunomodulators with anticoagulants (to combat the severe thromboses that appear to be a common by-product of the severe disease).

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

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

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

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

Confirmation of what was obvious to many of us.

(3) Miscellaneous updates:

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

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

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

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

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

(Quote)

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

(Twitter thread unrolled here)

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

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

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

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

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

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

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

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

Summarizing his remarks:

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

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

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

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

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

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

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

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

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

Consequently, meat prices are rising in Germany.

COVID19 update, VE-Day 2020 edition: software engineer on simulation code; what exactly does “peer-reviewed” mean?

Today, 75 years ago on May 8, 1945, World War Two ended in the European theatre with the unconditional surrender of Nazi Germany. “The instrument of surrender signed 7 May 1945 stipulated that all hostilities must cease at 23:01 (CET), 8 May 1945, just an hour before midnight.” However, since that was already past midnight, EET and Moscow time, the USSR and its satellite states marked VE Day on May 9, and Russia does so to this day. In Israel the day is unofficially marked on May 9, owing to the large number of elderly Russian immigrants who had actually fought in what Russians call “The Great Patriotic War”.

Meanwhile, some happenings on the COVID front.

(1) (Hat tip: masgramondou.) An experienced software engineer, formerly at Google, reviews Neil Ferguson’s simulation code in detail.Yes, the one that predicted two million dead in the US, which later had to be revised downward by a factor of twenty.. Read the whole thing, and weep. A few teasers:

My background. I wrote software for 30 years. I worked at Google between 2006 and 2014, where I was a senior software engineer working on Maps, Gmail and account security. I spent the last five years at a US/UK firm where I designed the company’s database product, amongst other jobs and projects. I was also an independent consultant for a couple of years. Obviously I’m giving only my own professional opinion and not speaking for my current employer.

The documentation says: “The model is stochastic. Multiple runs with different seeds should be undertaken to see average behaviour.” “Stochastic” is just a scientific-sounding word for “random”. That’s not a problem if the randomness is intentional pseudo-randomness, i.e. the randomness is derived from a starting “seed” which is iterated to produce the random numbers. Such randomness is often used in Monte Carlo techniques. It’s safe because the seed can be recorded and the same (pseudo-)random numbers produced from it in future. Any kid who’s played Minecraft is familiar with pseudo-randomness because Minecraft gives you the seeds it uses to generate the random worlds, so by sharing seeds you can share worlds.

Clearly, the documentation wants us to think that, given a starting seed, the model will always produce the same results.

Investigation reveals the truth: the code produces critically different results, even for identical starting seeds and parameters.

I’ll illustrate with a few bugs. In issue 116 a UK “red team” at Edinburgh University reports that they tried to use a mode that stores data tables in a more efficient format for faster loading, and discovered – to their surprise – that the resulting predictions varied by around 80,000 deaths after 80 days[…]

(2) “It’s not peer-reviewed!” You hear a lot in debates about COVID19 nowadays. But what does this really mean?

For a scientific paper to get published in a reputable scientific journal, it needs to undergo peer review: the editor (or an associate/section editor) sends the submitted paper out to (usually between two and four) experts in the field for their frank evaluation of the science. They write verbal reports, passed back anonymously to the author, and may also answer a questionnaire grading the paper on various criteria (novelty, technical correctness, quality of presentation, appropriate length,…). They also make a summary recommendation which is one of the following

  • Publish as is (rarely do all reviewers recommend this on 1st pass)
  • Publish subject to minor revisions detailed in the report. (Further review is typically not expected.)
  • May be publishable subject to major revision (and usually re-reviewing of the revised manuscript).
  • Not suitable for the journal, but may be publishable in _____
  • Not suitable for publication in any form

Where does one draw the line between “minor” and “major” revision? In practice, if (nontrivial amounts of) additional experiments/computer simulations/… are required, or if the interpretation needs to be radically overhauled, it’s considered “major”, otherwise minor. One round of the process easily takes a month or more, doubled if one or more reviewers insist on major revision, or if the paper is initially rejected and resubmitted to another journal. In fast-moving research areas (not just the present global pandemic), this causes frustrating delays. So sometime in the 1990s, when the web was still in its infancy, a group of particle physicists developed an online preprint server that, after a period under the rather confusing URL xxx.lanl.gov (which suggested a sideline of Los Alamos National Laboratory into adult entertainment), became known as arXiv.org. Here scientists could share their freshly submitted manuscripts with colleagues ahead of publication, or even circulate drafts. Anybody wishing to comment on such a “preprint” could just email the author.Over time, similar sites came online for the life sciences (biorxiv.org), medicine (MedRxiv.org) and finally chemistry (chemrxiv.org). Sure, there are spam and crank submissions to these sites (site managers try to keep out the obvious ones), but for the most part, submissions are legitimate papers in their original, pre-peer reviewed, form. Many of them, if the journal (publisher) allows this, update their submission with a “postprint”, i.e., the revised manuscript after peer review. (arxiv.org and similar sites are set up such that the original and revised uploads are always preserved and accessible, to forestall a “Oceania is not at war with Eurasia” scenario.) Many journals nowadays, once a paper is accepted for publication, immediately put the accepted manuscript “postprint” online, and in priority disputes this date counts as the date of first publication.

Copy editing by the production staff, typesetting in journal format, proofreading by the author (often with some last-minute changes) may take several weeks more, after which the final “version of record” comes online, often at first with placeholder page numbers ahead of inclusion in a journal issue. (No further change is made after this other than updating the placeholder page numbers to the final ones upon inclusion in an issue. If the authors find a mistake in their own paper at this point, their only option is to publish an erratum.)

Peer review is definitely valuable, and there may be substantial changes between an online preprint and the version of record — but that does not necessarily mean the preprint is worthless, especially if it comes from an established research group, in which case it’s best regarded as a “beta release” — some changes may be expected, but the paper may already be quite useful. The anonymous peer review system has its own issues with bias and (both benign and malignant) “gatekeeping”, but for the most part has served the scientific community well. Its primary weakness at this point is that qualified reviewers become over-burdened with manuscripts to review — keep in mind this is unpaid service to the scientific community, and reviewers quickly learn not to respond too fast, or they get “rewarded” with more refereeing requests. And after all, you need to perform, manage, and publish your own research, aside from teaching and any administrative duties you might have.

Alternatives have been sought. Public open peer review is one of them, where the reviewers’ reports and critiques are visible online. This could potentially become a hybrid alternative to both the preprint system and anonymous peer review, with radical transparency to the reader. In the discussion on the community testing effort in Santa Clara County, we saw an interesting example.

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

Busy day at work, so just some quick updates:

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

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

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

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

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

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

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

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

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

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

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

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

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

  • starting May 10, every household can receive and host four designated people (a fixed list of four). Recommended to sit outdoors. No travel distance limitation
  • May 11, shops will open. One customer per 10m^2 (110 sq.ft.) floor area. Wearing a mask is recommended but not mandatory; generally recommended in situations where 1.5m (5ft) distance cannot be maintained (e.g. on public transit). If lines develop, elderly, handicapped, and care workers get priority
  • public transit in principle reserved for people who have no private means of transportation (cars, motorcycles). In practice, this will not be enforced
  • restaurants, cafés, cultural centers remain closed for now
  • public sports events are put off until July 31

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

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

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