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

Very briefly after a long workday.

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

 

 

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

 

 

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

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

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

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

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

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

 

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

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

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

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

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

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

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

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

https://doi.org/10.1056/NEJMoa2016638

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

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

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

Anyway, let Dr. Seheult explain it himself:

 

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

COVID19 update, June 4, 2020: is the virus a picky eater; co-authors of influential Lancet hydroxychloroquine study retract paper

(1) Somebody quipped to me the other week: “the virus is a picky eater”. Now, Prof. Karl Friston of UC London, a well-known neuroscientist and computational modeler who is a member of “the independent SAGE committee” is interviewed here on UnHerd.

Now, from the unlikely source of a prominent member of the “Independent SAGE committee”, the group set up by Sir David King to challenge government scientific advice and accused by some of being populated with Left-wing activists, comes a claim that the true portion of people who are not even susceptible to Covid-19 may be as high as 80%.

 

A written essay is here. His thesis: 

Theories abound as to which factors best explain the huge disparities between countries in the portion of the population that seems resistant or immune — everything from levels of vitamin D to ethnic-genetic and social and geographical differences may come into play — but Professor Friston makes clear that it does not primarily seem to be a function of government coronavirus policy. “Solving that — understanding that source of variation in terms of this non-susceptibility — is going to be the key to understanding the enormous variation between countries,” he said.

Controversial? We link, you decide.

(2) The Washington Examiner reports that the influential The Lancet paper, which claimed hydroxychloroquine was more harmful than helpful in the treatment of COVID19 based on dodgy Surgisphere data, has now been retracted by 3 of the 4 authors (the 4th is the CEO of Surgisphere). Here is the original retraction notice:

https://www.thelancet.com/lancet/article/s0140673620313246

After publication of our Lancet Article,1 several concerns
were raised with respect to the veracity of the data
and analyses conducted by Surgisphere Corporation
and its founder and our co-author, Sapan Desai, in
our publication. We launched an independent third-
party peer review of Surgisphere with the consent of
Sapan Desai to evaluate the origination of the database
elements, to confirm the completeness of the database,
and to replicate the analyses presented in the paper.

Our independent peer reviewers informed us that
Surgisphere would not transfer the full dataset, client
contracts, and the full ISO audit report to their servers
for analysis as such transfer would violate client
agreements and confidentiality requirements. As such,
our reviewers were not able to conduct an independent
and private peer review and therefore notified us of their
withdrawal from the peer-review process.

We always aspire to perform our research in accordance
with the highest ethical and professional guidelines. We
can never forget the responsibility we have as researchers
to scrupulously ensure that we rely on data sources that
adhere to our high standards. Based on this development,
we can no longer vouch for the veracity of the primary
data sources. Due to this unfortunate development, the
authors request that the paper be retracted.

We all entered this collaboration to contribute
in good faith and at a time of great need during
the COVID-19 pandemic. We deeply apologise to
you, the editors, and the journal readership for any
embarrassment or inconvenience that this may have
caused.

The accompanying statement by the Lancet editorial board:

Statement from The Lancet
Today, three of the authors of the paper, “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis”, have retracted their study. They were unable to complete an independent audit of the data underpinning their analysis. As a result, they have concluded that they “can no longer vouch for the veracity of the primary data sources.” The Lancet takes issues of scientific integrity extremely seriously, and there are many outstanding questions about Surgisphere and the data that were allegedly included in this study. Following guidelines from the Committee on Publication Ethics (COPE) and International Committee of Medical Journal Editors (ICMJE), institutional reviews of Surgisphere’s research collaborations are urgently needed.

(3) Elsewhere in the Lancet is an article with a “meta-analysis” of other studies (in plain English: a study in which the raw data of several original lstudies are combined into a larger dataset and the statistical analysis repeated in order to achieve greater productive power than the individual studies)  on the effectiveness of distancing, face masks, and eye protection, in both  healthcare and non-healthcare (community) settings.

https://doi.org/10.1016/S0140-6736(20)31142-9

From the summary (paragraphing and emphasis mine):

Our search identified 172 observational studies across 16 countries and six continents, with no randomised controlled trials and 44 relevant comparative studies in health-care and non-health-care settings (n=25 697 patients).

Transmission of viruses was lower with physical distancing of 1 m or more, compared with a distance of less than 1 m (n=10 736, pooled adjusted odds ratio [aOR] 0·18, 95% CI 0·09 to 0·38; risk difference [RD] –10·2%, 95% CI –11·5 to –7·5; moderate certainty); protection was increased as distance was lengthened (change in relative risk [RR] 2·02 per m; p_interaction=0·041; moderate certainty).

Face mask use could result in a large reduction in risk of infection (n=2647; aOR 0·15, 95% CI 0·07 to 0·34, RD –14·3%, –15·9 to –10·7; low certainty), with stronger associations with N95 or similar respirators compared with disposable surgical masks or similar (eg, reusable 12–16-layer cotton masks; p =0·090; posterior probability >95%, low certainty).

Eye protection also was associated interaction with less infection (n=3713; aOR 0·22, 95% CI 0·12 to 0·39, RD –10·6%, 95% CI –12·5 to –7·7; low certainty).

Unadjusted studies and subgroup and sensitivity analyses showed similar findings.

 

ADDENDUM: “WHO frustrated by China’s info delays as coronavirus started to spread, report finds”. Is this damage control/reputation management on the part of the WHO, or the genuine expression of frustration by the technical levels of the organization? More about this tomorrow, G-d willing.

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

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

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

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

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

Here’s another good one:

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

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

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

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

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

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

 

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

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

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

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

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

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

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

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

Pirkei Avot 1:11

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

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

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

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

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

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

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

COVID19 update, May 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, April 25, 2020: doctor videos edition

Good morning, happy weekend, shabbat shalom. In today’s update, mostly videos, which I’m linking rather than embedding (as a workaround for a WordPress dot com editor bug).

(1) Mike Hansen MD reviews COVID19 drug trials. He’s bearish on HOcq (2/10) but surprisingly bullish on ARBs (angiotensin II receptor blockers, 7/10) and to a lesser extent ACE inhibitors (5/10), both types of drugs in established use as antihypertensives. For remdesivir: great results in Chicago leaked, less so in Mass (7/10). Favipiravir [sold in Japan as AVIGAN as an anti-influenza drug] targets RdRp (6/10). IL-6 inhibitors:  tocilizumab (approved for managing cytokine storm, used in severe RA and in immunotherapy complications): expensive, potent immunosuppressants (5/10).  

His top 5: Recombinant ACE2 (8/10); ARBs tied with remdesivir (7/10) and favipiravir/Avigan (7/10); Umifenovir/Arbidol (6/10)

(2) Via reader Dawn Miller, a two-part interview by a local ABC affiliate with Dr. Dan Erickson, operator and chief physician of Accelerated Urgent Care in Bakersfield, CA. Among many other things, he is saying that, at least at this point, the lockdown in CA is doing much more harm than the disease itself.

• Part 1 (bulk of the interview)
• Part 2 (Q&A segment after length limit reached)

On a tangentially related note, a medical source in Belgium told me that, while they never did the “shut everything down to make room for COVID19 patients” thing, they notice a steep drop in patients coming in with suspected cardiovascular and cerebrovascular complaints, and like their German colleagues, they can’t believe “heart attacks and strokes are suddenly 30% less frequent”. They believe they’ll have huge “medical cleanup bills” on deferred care cases. He also told me that in the grey area of urgency, access to care can be problematic: he gave the concrete example of a tooth abscess in an elderly patient with a pacemaker. As pericarditis is a not-uncommon complication of dental surgery in such “risk patients”, he referred the octogenarian to an oral surgeon at the local hospital — but the department was closed due to COVID19. “Just take antibiotics.”

(4) Miscellanea:

• U. of Washington doing new hydroxychloroquine trial, but now seeing if it can stop mild cases from becoming severe;
• (h/t: Erik Wingren) fatal strokes showing up in young coronavirus patients?! (WaPo; archive) We know (see, e.g., Dr. Seheult’s video I’ve been linking) that blood clotting in the lungs is one phenomenon occurring during severe COVID19, hence prophylaxis regimes of some doctors include mild anticoagulants/antithrombotics like low(ish)-dose aspirin. Note that at least here, many doctors start prescribing the latter to patients for cardio- and cerebrovascular prophylaxis when the patients reach their fifties: these younger patients would not yet have been on them.
• Marc Andreessen  [of Mosaic/Netscape fame, and now Andreessen Horowitz]: It’s Time To Build
• Belgium update: politicians accelerate the unlock time table, reports De Standaard (in Dutch): the 2nd phase has been moved from May 18 to May 11.
• A community immunity testing effort by the University of Geneva Hospital is reported on here (in French). More later perhaps on this, but as of April 17, they found that 5.5% of testing subjects had antibodies for COVID19. Again we see a very substantial Dunkelziffer/”dark number”/stealth infection rate: on the same day, total known COVID19 cases accounted for just 0.3% of the Swiss population, though I don’t have numbers for Geneva specifically.
• DIE WELT (in German) reports on the situation in the mostly-immigrant Paris suburbs of the 93rd Département, where workers in both the formal and “informal” economies have been pushed out of work. Even the Préfect (chief administrator of a Département, somwhere between a County Judge and a Governor in US parlance) takes seriously the possibility of food riots.

UPDATE: via David S. Bernstein, a profile of Stanford statistician John Ioannides (WSJ behind paywall, archive copy here).

COVID19 update, April 23, 2020: community immunity testing results from Belgium; non-COVID19 hospital care; India

(1) DE STANDAARD (in Dutch) reports on a new immunity study in Belgium. Researchers from the University of Antwerp collected residual blood samples of 3,686 patients that had originally been taken for other purposes (e.g., to check for anemia) and checked those for COVID19 antibodies. The samples were collected on March 30.

The Antverpian team found that about 3% of the samples had antibodies — if their sample were truly representative, that would imply about 300,000 people had antibodies for COVID19 around March 30. 

Let’s work with this a bit, shall we? According to worldometers, on that date (March 30) Belgium had 11,899 documented cases. This implies a Dunkelziffer/“dark number” (De Standaard uses this English term) to documented cases ratio of about 25:1.

As of April 22, Belgium had 41,889 documented cases — if we (dubiously) assume that the “dark number” ratio is constant, then about 10.6% of the population may have antibodies at present. 

How much would you need for herd immunity? The herd immunity threshold %HI depends in a very simple way on the effective reproductive number R of the virus: 

%HI = 100% * (1 – 1/R)

If R≤1 then the epidemic will die out anyway and %HI is zero. For R=1.1 just 9% would already be enough, while for R0=1.5 you’d need 33%, for R=2 you’d need 50%, and for R=2.5 you’d need 60%.  (Corollary: if Belgium does have about 10-11% with antibodies, it doesn’t need to keep R below 1.0 with social distancing measures, but can let things slide a little higher. As the percentage of immune residents grows, further relaxation is possible.)

(2) At Sarah Hoyt’s blog, a guest post by “Scarlett Doc” called “Healthcare Charlie Foxtrot” about the current situation in US hospitals for non-COVID19 care. These are the fruits of rigid edicts by domineering, not-too-bright bureaucrats: entire hospitals sitting on their hands waiting for the COVID19storm to hit (which is largely confined to NYC and a few other hotspots), while myriad non-COVID19 patients go untended. There are even hospitals furloughing most of their medical staff. The article is aptly illustrated with a picture of a dumpster fire. Read and weep.

It gets bad enough even without meddlesome middlebrow bureaucrats with Messiah complexes. German hospitals by and large continued normal operations. Yet DIE WELT (in German) reports on how internal medicine wards in German hospitals see such a drop in admissions for their “big 3” emergencies (heart attacks, strokes, and appendicitis) that it is making doctors suspicious. https://www.welt.de/vermischtes/article207436223/Corona-Deutlich-weniger-Patienten-in-der-Kardiologie-Aerzte-werden-stutzig.html 

“It cannot be that we suddenly have 30% fewer strokes than usual because of corona” says one — so they suspect patients are staying away when they shouldn’t, out of fear of contracting COVID19. “In 2018 there were 210,000 heart attacks and about 300,000 strokes in Germany. That these numbers have suddenly contracted because of the Corona-epidemic, nobody in the medical community believes.”

(3) (Hat tip: Alex W.) Quartz India wonders why the remarkably low toll in India. A young population pyramid is a plus, but against that stand two minuses: multigenerational families and high incidence of chronic diseases even among fairly young people. Then again, the weather being very hot and humid (bad for the virus), universal BCG vaccination, and broad (hydroxy)chloroquine use in areas where malaria is endemic could all be factors. (Incidentally, monsoon season in India is flu season there, so we could see a surge then.)

Related, however, a recent preprint claims that the BCG differential is “an illusion created by testing”: https://www.medrxiv.org/content/10.1101/2020.04.18.20071142v1

(4) Finally, could the serine protease nafamostat (an anticoagulant that also has some antiviral properties) be a drug candidate for COVID19? A Japanese group shows in vitro evidence in this preprint: https://www.biorxiv.org/content/10.1101/2020.04.22.054981v1

UPDATE: Matt Ridley, popular science writer and member of the House of Lords, gives a layman-friendly overview of COVID19 drug candidates in the special 10,000th issue of The Spectator.

COVID19 update, April 7, 2020: hemoglobin, COVID19, and hydroxychloroquine; miscellaneous updates

A potentially HUGE finding in a preprint suggests a radically different mechanism for hydroxychloroquine’s action in COVID19. TL;DR in layman language: that a lot of the hypoxyia (oxygen starvation) of severe COVID-19 patients is due to hemoglobin in red blood cells being disrupted by the virus (as it is by the malaria pathogen), and that hydroxychloroquine protects hemoglobin in both diseases. A layman’s discussion can be found here.

“Masgramondou” has an origin hypothesis for the outbreak that sounds disturbingly plausible to anyone who subscribes to the “incompetence before malice” or “c*ck-up before conspiracy” principle.

How helpful is soap against COVID-19? If yes, why? The American Chemical Society has a helpful YouTube video https://www.youtube.com/watch?v=K2pMVimI2bw

The leader article of German center-right daily Die Welt is entitled: “the end of globalization as we know it” https://www.welt.de/wirtschaft/article207072567/Corona-Krise-Unternehmen-aendern-ihre-Lieferketten.html

Ventilator outcomes discussed by Roger Seheult MD https://www.youtube.com/watch?v=uaIzj3s3p4A&t=7s . In another video, he weighs in on the beneficial effect of sauna baths for immunity in general and in COVID-19 in particular  https://www.youtube.com/watch?v=EFRwnhfWXxo (hat tip: Mrs. Arbel) Finnish statistics so far look enviable.

My friend Tom Knighton lives in  Dougherty County in rural GA, which found itself coping with a fierce COVID-19 outbreak following a “super-spreader” event at a funeral. But it seems they are now seeing the proverbial light at the end of the tunnel. https://www.walb.com/2020/04/05/phoebe-releases-sundays-covid-numbers/

Israel, which saw super-spreader events during Purim parties a month ago, is now taking the drastic step of imposing a curfew from a few hours before the Passover seder until the next morning. Seders are to be done strictly in the home, nuclear family only, no guests. 

Japanhttps://www.worldometers.info/coronavirus/country/japan, which was very reluctant to do so, finally declares pandemic emergency

And Instapundit minces no words in USA Today .

UPDATE: via David Bernstein, interactive COVID-19 map of the New York City metropolitan area. Counterintuitively, Manhattan is not the worst hit pro capita: that extremely dubious honor falls to the nearer commuter counties.
NY Gov. Andrew Cuomo, hovewer, points to an apparent “flattening of the curve” in hard-hit NYC.

COVID19 update, March 29, 2020: two brief items+new French hydroxychloroquine study

Day job (remotely) absorbed my day, so today I only have two brief items

(1) (H/t: a friend): Systems biologist, Prof. Ron Milo from the Weizmann Institute has released coronavirus by the numbers, with nearly daily updates. The “numbers” are accompanied by explanatory text written in a way that non-biologists can follow it — not “obscured by clouds” of jargon.

(2) I had an online conversation with a leading neuroscientist about our response to stress in such a situation. In a nutshell: our stress response system is optimized for a very different scenario: a lion or pack of wolves coming after you. Heart rate and blood pressure going up, blood sugar and cortisol levels… all great if you need your running speed and reflexes boosted to escape from a predator.

The trouble is with more diffuse, long-term threats like a COVID19 epidemic leading to “chronic stress”. The results is anxiety, sleep deprivation, depressed immune response, … He suggested meditation [his response when I suggested old-school Jewish prayer instead was rather bemused ;)], exercise (even in the house if confined there, outdoors if possible), and any sort of enrichment activity that you derive joy from.
At my observation that obsessive news readers may simply have to “ration” the news updates, since it’s possible to be distracted 24/7 by them and kept in a permanent state of anxiety, the neuroscientist nodded.

(3) Via Instapundit: The same French team at the Mediterranean Institute for Infectious Diseases in Marseille, which reported an initial pilot clinical trial with an hydroxyquinoline-azithromycin combo now has a larger study out:

In 80 in-patients receiving a combination of hydroxychloroquine and azithromycin, the team found a clinical improvement in all but one 86 year-old patient who died, and one 74-year old patient still in intensive care unit. The team also found that, by administering hydroxychloroquine combined with azithromycin, they were able to observe an improvement in all cases, except in one patient who arrived with an advanced form, who was over the age of 86, and in whom the evolution was irreversible, according to a new paper published today in IHU Méditerranée Infection.

“For all other patients in the cohort of 80 people, the combination of hydroxychloroquine and azithromycin resulted in a clinical improvement that appeared significant when compared to the natural evolution in patients with a definite outcome, as described in the literature. In a cohort of 191 Chinese inpatients, of whom 95% received antibiotics and 21% received an association of lopinavir and ritonavir, the median duration of fever was 12 days and that of cough 19 days in survivors, with a 28% case-fatality rate (18),” the research team said.

The team went on to say: “Thus, in addition to its direct therapeutic role, this association can play a role in controlling the disease epidemic by limiting the duration of virus shedding, which can last for several weeks in the absence of specific treatment. In our Institute, which contains 75 individual rooms for treating highly contagious patients, we currently have a turnover rate of 1/3 which allows us to receive a large number of these contagious patients with early discharge. Chloroquine and hydroxychloroquine are extremely well-known drugs which have already been prescribed to billions of people.”

“In conclusion, we confirm the efficacy of hydroxychloroquine associated with azithromycin in the treatment of COVID-19 and its potential effectiveness in the early impairment of contagiousness. Given the urgent therapeutic need to manage this disease with effective and safe drugs and given the negligible cost of both hydroxychloroquine and azithromycin, we believe that other teams should urgently evaluate this therapeutic strategy both to avoid the spread of the disease and to treat patients before severe irreversible respiratory complications take hold,” the team concluded.

Preprint online at https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf

Related, Carmi Sheffer, an Israeli doctor working in Italy shares some experiences in the Times Of Israel.

In Padua, the autoimmune medicine Tocilizumab has proven effective, but can only be used once it is established that no other viruses or bacteria are present in the patients’ bodies, he said. The hospital where he works has also seen positive results from the antiviral drug Remdesivir, he added.

[…] One technique he said had yielded dramatic results was to have patients lie on their stomach instead of on their back while on a ventilator. “Suddenly the oxygen level in the blood jumped [up],” he said.

[A source in Belgium told me they had started doing this as well.]

Dr. Sheffer believes, “I think the worst is behind us. We will control the virus and flatten the curve within a few weeks, but the closure will continue until June,” he predicted.