T cells are a type of white blood cells that are specialized in recognizing infected cells, and are an essential part of the immune system. About 1 to 5 percent of T cells in the blood of healthy people consist of so-called MAIT cells (mucosa-associated invariant T cells), which are primarily important for controlling bacteria but can also be recruited by the immune system to fight some viral infections.
In this study, the researchers wanted to find out which role MAIT cells play in COVID-19 disease pathogenesis. They examined the presence and character of MAIT cells in blood samples from 24 patients admitted to Karolinska University Hospital with moderate to severe COVID-19 disease and compared these with blood samples from 14 healthy controls and 45 individuals who had recovered from COVID-19. Four of the patients died in the hospital.
The results show that the number of MAIT cells in the blood decline sharply in patients with moderate or severe COVID-19 and that the remaining cells in circulation are highly activated, which suggests they are engaged in the immune response against SARS-CoV-2.
“The findings of our study show that the MAIT cells are highly engaged in the immunological response against COVID-19,” Johan Sandberg says. “A likely interpretation is that the characteristics of MAIT cells make them engaged early on in both the systemic immune response and in the local immune response in the airways to which they are recruited from the blood by inflammatory signals. There, they are likely to contribute to the fast, innate immune response against the virus. In some people with COVID-19, the activation of MAIT cells becomes excessive and this correlates with severe disease.”
(2) “Casey”, a contact on FB asked about PCR running abnormally high numbers of amplification cycles—up to 45—and whether that isn’t basically “running until you test positive”. “Lissa K.” points to this NYT (!) piece which I’ve had on the blog earlier, “Your test is positive — maybe it shouldn’t be” and at least one senior doctor in Israel, Dr. Amir Shachar who runs the Emergency Medicine department at Laniado in Netanya, has said the same about our own labs. Jordan Schachtel discusses the false positives for NFL players found this way (and eventually set aside). From an interview with the NFL Chief Medical Officer (screenshot from the article):
(3) The more I see of our new Health Minister, Yuli Edelstein, the more he strikes me as a “Politruk”. He is probably more responsible for the mess we are in now than anybody else on the political level. Had he not fought tooth and nail to keep “track and trace” under the auspices of a health machinery that clearly was overwhelmed, and had this been transferred to the IDF months ago over Edelstein’s veto, methinks we could have dammed in our current outbreak much earlier.
(1) Israel’s “coronavirus czar” Prof. Roni Gamzu apologizes for failing to prevent a second lockdown. At least this writer realizes he did what he could. As the Yes song goes, “Yours Is No Disgrace“. Even PM Netanyahu, uncharacteristically, admitted failure in handling the epidemic “by reopening too soon, too fast”. I frankly think one person who could do with reciting a few additional “al chet”s this kippur is Health Minister Yuli Edelstein, for the foundering of the “track and trace” effort because of turf wars between the health establishment (claiming it needed to be run by health professionals) and those (starting with former Defense Minister Naftali Bennett) who correctly recognized it as a logistical and scalability challenge first and advocated from the start for its transfer to the IDF.
(3) Prof. Mark Last from Ben-Gurion University claims Israel is approaching herd immunity. Some of the papers I have been discussing here figure in the article. Also quoted is Tom Britton, who argues for a number of 43%, in between the classical first-order estimate of 60+% and the second-order estimate of Prof. Gabriela Gomes, who arrives at numbers in the 20-25%.
(4) Interesting interview with British epidemiologist Michael Edelstein, who recently immigrated to Israel. Read the whole thing: I can’t do it justice by selective quoting.
The blog will now observe “radio silence” until after the holiday.
May you be sealed in the Book of Life on this Yom Kippur. Those of you who do fast, have an easy fast. And great health in mind and body to us all.
Some of you may be old enough to remember a singing nun from Belgium on the Ed Sullivan Show, performing her surprise hit “Dominique” that sat at the top of the US charts for four weeks and went on to win a Grammy Award. Her real name was Jeanne Deckers: she went by the stage name Soeur Sourire (literally, Sister Smile).
She was born to a master confectionary baker and his strict wife in the town of Laeken, where the Royal Palace stands. (According to some sources, her parents were strict Catholics, but according to an article in the French Catholic paper La Croix, she grew up with a secular humanist background and came to religion on her own.)
Always something of a tomboy, she was very active in the Belgian version of the Girl-scouts. Her parents’ wish was that she would get married and take over the family business, but she decided that life wasn’t for her and literally got herself to the nunnery.
The new novice was well liked, especially her singing —and as one of the few worldly possessions she was allowed to keep was a portable musical instrument, she got an acoustic guitar and learned to play it well enough to accompany herself. Her superiors actually encouraged her to perform, and somehow a tape of her got played to an A & R person at the Philips record label (a subsidiary of the electronics giant) .
They immediately latched upon this one catchy song, which most non-Catholics (myself included: this isn’t exactly my musical cup of tea) don’t realize is actually a paean to the eponymous founder of the Dominican Order (to which her monastery belonged).
That it became a hit in Belgium and France was not that much of a surprise: that a song in French would climb to the top of the charts in the USA definitely was. An American tour and a successful first album followed.[French Wikipedia claims the “Dominique-nique-nique” chorus was risqué, since in modern French slang “niquer” means “to scr*w” —- but I believe this became common colloquial French only long after she was dead, slipping in from Arabic via North African immigrants.]
Anyway, during Vatican II and its aftermath she became disillusioned with monastic life and with her church’s religious establishment more generally, and sought a new way that she thought would be more relevant to today’s world. Her song lyrics also took on a more provocative character, praising contraception and excoriating what she called “con-conservateurs” (conservative c**ts/*ssholes). To cut a long story short, confrontations with her order were inevitable and eventually she was voluntarily laicized.
And now her troubles truly began — not with her former religious superiors but with the Belgian tax authorities. They came after her for back taxes on “her” royalties — of which she had never seen a penny. After all, she had made vows of poverty, so the 5% or so that would have been hers were kept by her monastery, with Philips keeping the remainder for themselves. Her pleas fell on deaf ears with the tax authorities, and Philips argued that they had discharged their obligations according to the contract.
Her monastery bought or donated her an apartment in Wavre, in exchange for signing a document relinquishing all further claims and agreeing not to slander the order in public. She went to live there with a former classmate, a therapist working with autistic children named Annie Pecher. (It is pretty clear that the relationship between them was no ordinary friendship but an amitié particulaire, as the French euphemism goes — although they always denied that it had a physical component.)
They started a school for autistic children named Claire-Joie (“clear joy”), but sank ever further in debt, with no hope of ever paying the Belgian tax authorities back. (I am not a Belgian tax lawyer, but I believe this would have been an easily winnable case.)
All her attempts to reboot her singing career, in order to generate income, met with failure — the last attempt was a collaboration with Belgian electronic music pioneer and producer Marc Moulin (of “Telex” fame).
The couple sank into depression fueled by alcohol and prescription medications. After their school went bankrupt, they took their lives in a suicide pact. They left detailed instructions on each item in the apartment whom to give it to, and how they wished to be buried together.
Moral of the story: salvation may be just around the corner when you feel you absolutely are “done”. In the immortal last words to the House of Commons of WInston Churchill: “Never flinch, never weary, never despair.”
ADDENDUM: Kudos to D. Jason Fleming, who drew my attention to parallels with the case of “Golden Age” science fiction and alternate history writer H. Beam Piper. “He committed suicide, leaving a note apologizing for the mess, never knowing that his agent, who had died a short time before, actually sold a number of stories and books of his, which would have erased the problems that led him to do it in the first place.”
[I am blessed to have a number of readers who scour the primary and secondary biomedical literature for interesting articles and tip me off to them. Many thanks, much appreciated.] (1) (Hat tip: Jeff Duntemann) A Spanish study appears to show a statistical link between zinc deficiency and mortality among COVID19 hospital patients.
Also via Jeff Duntemann: two blog posts (here and here) about a zinc ionophore that appears to be more effective as such than hydroxychloroquine and — get this — is a component of a hot beverage already consumed daily by hundreds of millions of people in East Asia: green tea.
Taking Clioquinol (CQ) as the standard, as is its the most potent ionophore we have tested in our liposomal assay, and assigning a 100% value to the clioquinol ionophoric activity , then pyrithione (PYR), which is not a polyphenol, displays also almost a 100% activity relative to clioquinol, whereas epigallocatechin gallate (EGCG) has 60% activity and quercetin (QCT) has only 30% the efficiency of clioquinol, on a equimolar basis.Nonetheless, this is a proof of concept assay, and exact ionophoric capacity of each compound will vary with the absolute and relative concentrations of the ionophore and of zinc; it will also depend on temperature, pH of the solution and lipid composition of the liposome (absolute and relative amounts of lecithin, other phospholipids, cholesterol, etc). It will also vary dependent on the fluorochrome used to detect zinc in the interior of the liposome (FluoZinc, Zinquin, etc) and on the concentration of the fluorochrome within the liposome, since different fluorochromes display different strengths to separate zinc from the polyphenol zinc complex.
In any case, in the exact standardized conditions used in our assay, we can conclude the relative ionophoric effect of the different compounds tested.It is, I think, important to remark that the liposomal assay allows to elaborate a scale or a standard of ionophoric strength or ionophoric capacity or potential; and that, once established through this assay that a compound behaves as an ionophore in a liposome, we can say that it will also be ionophoric in any type of cell, as this effect is independent of content of protein, glycoprotein, glycolipids, of the cell membrane, although of course it will vary according to the fluidity of the cell membrane, that depends on its exact lipid composition.
The interviewer asked Dr. Larrea how well zinc is absorbed by cells in the absence of an ionophore. His answer:
Zinc, 10 micromolar (Zn10), alone, by itself, renders just circa 2% fluorescence of that obtained with CQ. Control means, fluorescence of liposomes without the addition of any substance. That means that zinc alone, by itself is not able to enter the liposomes, as expected. This 1-2% is the background fluorescence of the whole system.
Bioavailability of EGCG from oral ingestion (read: drinking green tea) appears to be somewhat problematic though. Then again, this is definitely in the category of “can’t hurt even if it won’t help”.
(2) In my inbox I found an older message by “Yves not-Cohen” mentioning a review article in a cardiology journal, “QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review” by Lior Jankelson et al., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211688/
Note that these doctors are not saying: “ZOMG! This drug is poison and teh debbil!” but, rather more prudently:
[… from] data on 1515 COVID-19 patients. Approximately 10% of COVID-19 patients treated with these drugs developed QT prolongation. We found evidence of ventricular arrhythmia in 2 COVID-19 patients from a group of 28 treated with high-dose chloroquine. Limitations of these results are unclear follow-up and possible publication/reporting bias, but there is compelling evidence that chloroquine and hydroxychloroquine induce significant QT-interval prolongation and potentially increase the risk of arrhythmia. Daily electrocardiographic monitoring and other risk mitigation strategies should be considered in order to prevent possible harms from what is currently an unproven therapy.
“Torsades de pointes“, BTW, reads like a ballet term, but is the term a French cardiologist first used in 1966 for a specific types of cardiac arrhytmia, and has since become the standard term (“twisting of peaks”, literally). “Torsades occurs as both an inherited (linked to at least 17 genes) and as an acquired form caused most often by drugs and/or electrolyte disorders that cause excessive lengthening of the QT interval.“
ICAM isn’t a new drug, it’s an acronym for a combination of existing medications used simultaneously on patients. It uses Immunosupport drugs (Vitamin C and Zinc), Corticosteroids against inflammation, Anticoagulants against blood clots, and Macrolides to help fight infection.
As discussed here previously, multiple studies (including the English RECOVERY trial) have already come out in support of corticosteroids like dexamethasone, and there is enough evidence for blood clotting that a number of places are already applying anticoagulants. Vitamin C and zinc seems sensible as immune system boosters — though I would have added vitamin D or its first metabolite to the cocktail. Finally, macrolide antibiotics like azithromycin probably are more effective in preventing secondary bacterial pneumonia than in combating the viral infection.
To my Jewish readers, gmar chatima tova and have an easy fast if you observe one for Yom Kippur.
(1) (H/t: Instapundit) The Centers for Disease Control, which has a very detailed website, published a report that contains new “best estimates” for infection fatality rates, broken down by age group. According to Table 1, last column:
ages 0 tot 19: 0.003% (i.e., 1 in 33,333) ages 20-49: 0.02% (1 in 5,000) ages 50-69: 0.5% (1 in 200) 70 and over: 5.4% (alas, 1 out of 19)
Especially the figures for the young and fairly young are way lower than what the average person on the street has picked up from the sensationalist media.
The same report claims an estimated asymptomatic infection rate of 40%, but it could be as low as 10% or as high as 70%. Let that sink in for a moment: of 10 people who get infected, 7 will never even notice being ill. (My guess is their T-cell system works properly and nips the infection in the bud. T-cell immunity weakens with age…)
(2) The Wall Street Journal has an article on how people in the hard-hit Northern regions of Italy are coping with the aftermath of the lockdown. While current regulations there are pretty lenient, the population exercises caution of its own initiative, moving activities outdoors even when it is not required, and avoiding crowded places. Also, the common reliance on grandparents as “unpaid babysitters” has been toned down a little.
Months after Italy’s lockdown against the coronavirus ended, Enrica Grazioli still sanitizes everything that comes into her Milan apartment, wears face masks diligently and limits interactions between her sons and their grandparents. […] Ms. Grazioli, a self-proclaimed social butterfly who loves to cook for guests, still hasn’t had friends over for dinner since the virus struck. “Am I overdoing it?” says Ms. Grazioli. “Maybe, but we had a national tragedy of epic proportions and you don’t quickly forget something like that.” […] Italy, the first nation outside Asia to suffer a major coronavirus outbreak, had one of the world’s worst death tolls this spring. Overflowing hospitals in parts of northern Italy had to choose which patients got the last intensive-care beds. The Italian army drove truckloads of victims out of the city of Bergamo, which couldn’t cope with the dead. […] That shocking experience helps explain why Italy is so far having greater success than many other European countries in limiting the pandemic’s second wave.
I frankly also think that many of the hardest-hit towns in Italy being infected at near-herd immunity levels has a lot to do with it. Witness:
The percentage of tests that come back positive—a measure of whether testing is sufficiently comprehensive—is 2.1% in Italy, higher than it was in June but lower than in most of Europe, according to official data. A low positivity rate indicates that testing is widespread and not restricted to people who show symptoms. The World Health Organization recommends a positivity rate of 5% or less as a condition for reopening.
The percentage of positive tests is lower still in Lombardy, the epicenter of Italy’s pandemic, according to the regional government.
In Spain, by comparison, government data shows 11.9% of tests are positive, suggesting many infections go undetected.
“Reynaert”, one of my sources in Belgium, pointed to an article from De Standaard (in Dutch) discussing the second wave there — and how the province of Limburg, which was so hard-hit in the first wave, is now doing well in part because people are quite cautious.
(3) A libertarian think tank has picked up the English translation of an open letter by a group of Belgian doctors who are calling on the government to discontinue disruptive social distancing mandates and instead to adopt the Swedish model, rather than ruin the economy (and public health other than COVID19). The English version is definitely worth a read.
(4) Israel’s “lockdown lite” changes to a more severe lockdown starting tomorrow at 2pm local. Escalating hospitalizations, and “unprecedented” positive testing figures led to this move: PM Netanyahu wanted to impose it now, as an escalation of the existing lockdown, because this is a Jewish holiday season where stores are closed several days anyhow and people often take many of the remaining days off. Hence the economic cost is lighter than to have to do it anyhow after the current lockdown.
One goal is to bring down new infection figures to a range that the “track and trace” system can manage. Privacy concerns aside (not that Israelis are very privacy-minded to begin with), South Korea and Taiwan have shown this is one way to “tame” an epidemic without lockdowns (in this case, further lockdowns).
ADDENDUM: the “KAN” news had a segment (in Hebrew) about the situation at the HaEmek [“The Valley”] hospital in the town of Afula (North of the West Bank). They are currently full up on one corona ward, the reserve ward has room for another 10 patients if they do not require respirators. Some of the patients on the ward actually only have mild corona but are in hospital for other ailments and cannot be placed in general hospital population lest they infect staff and patients. (Mild corona cases who otherwise have no need to be in hospital are generally kept at home or in a “corona hotel”, as per their preference.) An (Arab Israeli) doctor being interviewed explains the difference between the two waves: “The first time around, we saw mostly Jews: returned from trips abroad, or got infected at Purim parties. Also some Arabs returning from Turkey. This time around? 90% Arabs. Most got infected at mass wedding parties. This is the result of taking things lightly and of fatalism. (He did not use the term “inshallah” but paraphrased it.)
Their local positive rate on tests is 15% —- in another segment, we are told that the rate in Arab East Jerusalem is 18%, vs. 10.5% national average.
In a third segment, we hear that the Rambam academic hospital in Haifa opened its emergency underground ward (originally meant for war or mass casualty events), adding capacity for 110 COVID patients immediately, with maximum capacity of up to 700 patients (of which some 170 can be on respirators).
METHODS We carried out a population-based study among 4.6 million members of Clalit Health Services (CHS). We collected results from vitamin D tests performed between 2010 and 2019 and used weighted linear regression to assess the relationship between prevalence of vitamin D deficiency and Covid-19 incidence in 200 localities. Additionally, we matched 52,405 infected patients with 524,050 control individuals of the same sex, age, geographical region and used conditional logistic regression to assess the relationship between baseline vitamin D levels, acquisition of vitamin D supplements in the last 4 months, and positive Covid-19. RESULTS We observe a highly significant correlation between prevalence of vitamin D deficiency and Covid-19 incidence, and between female-to-male ratio for severe vitamin D deficiency and female-to-male ratio for Covid-19 incidence in localities (P<0.001).In the matched cohort, we found a significant association between low vitamin D levels and the risk of Covid-19, with the highest risk observed for severe vitamin D deficiency. A significant protective effect was observed for members who acquired liquid vitamin D formulations (drops) in the last 4 months.
p<0.001 means: less than one chance in a thousand that the different results in the two groups were due to coincidence
Just how prevalent is vitamin D deficiency really in sunny Israel? Table 2 from the preprint: look at the percentages for the first row (less than 30 nanomol per liter). As you can see, it’s relatively rare among the general population, more common in the chareidi (“ultra-Orthodox”) sector, where more of life is spent indoors and both men and women cover most of their skin for reasons of “tzniut” (modesty) — and very common among Arab women (2.6 times more than their male counterparts)…
Dr. Campbell mentions something I’ve discussed here previously: counterintuitively, the problem is much less common in Scandinavia countries than in, say, Spain or Northern Italy. Quite simply: Scandinavians know they will get in trouble in winter unless they fortify their diet with vitamin D (I don’t think I’ll ever forget seeing a bottle of cod liver oil and shot glasses at a breakfast buffet in northern Norway). Northern Italians and Spaniards get enough in summer but falsely assume they won’t need any supplements in winter…
(2) Wendover Productions, a YouTube channel focusing mostly on logistics and the airline industry, has a new video looking at some of the logistical complexities of massive vaccine distribution on a short time scale:
Read the whole thing (it’s open access), but just a few highlights:
Even in local areas that have experienced some of the greatest rises in excess deaths during the covid-19 pandemic, serological surveys since the peak indicate that at most only around a fifth of people have antibodies to SARS-CoV-2: 23% in New York, 18% in London, 11% in Madrid.123 Among the general population the numbers are substantially lower, with many national surveys reporting in single digits[…] Yet a stream of studies that have documented SARS-CoV-2 reactive T cells in people without exposure to the virus are raising questions about just how new the pandemic virus really is, with many implications.
In a study of donor blood specimens obtained in the US between 2015 and 2018, 50% displayed various forms of T cell reactivity to SARS-CoV-2.511 A similar study that used specimens from the Netherlands reported T cell reactivity in two of 10 people who had not been exposed to the virus.7
In Germany reactive T cells were detected in a third of SARS-CoV-2 seronegative healthy donors (23 of 68). In Singapore a team analysed specimens taken from people with no contact or personal history of SARS or covid-19; 12 of 26 specimens taken before July 2019 showed reactivity to SARS-CoV-2, as did seven of 11 from people who were seronegative against the virus.8 Reactivity was also discovered in the UK and Sweden.
In fact, the article points out, “we’ve been in this movie before”
SWINE FLU DEJA VU. In late 2009, months after the World Health Organization declared the H1N1 “swine flu” virus to be a global pandemic, Alessandro Sette was part of a team working to explain why the so called “novel” virus did not seem to be causing more severe infections than seasonal flu.12
Their answer was pre-existing immunological responses in the adult population: B cells and, in particular, T cells, which “are known to blunt disease severity.”12 Other studies came to the same conclusion: people with pre-existing reactive T cells had less severe H1N1 disease.1314 In addition, a study carried out during the 2009 outbreak by the US Centers for Disease Control and Prevention reported that 33% of people over 60 years old had cross reactive antibodies to the 2009 H1N1 virus, leading the CDC to conclude that “some degree of pre-existing immunity” to the new H1N1 strains existed, especially among adults over age 60.15
The data forced a change in views at WHO and CDC, from an assumption before 2009 that most people “will have no immunity to the pandemic virus”16 to one that acknowledged that “the vulnerability of a population to a pandemic virus is related in part to the level of pre-existing immunity to the virus.”17 But by 2020 it seems that lesson had been forgotten.
Furthermore, Doshi goes into recent studies that reconsider the herd immunity threshold from a mathematical point of view
Nearly 50 years later, Gabriela Gomes, an infectious disease modeller at the University of Strathclyde, is reviving concerns that the theory’s basic assumptions [behind the common first-order herd immunity estimate] do not hold. Not only do people not mix randomly, infections (and subsequent immunity) do not happen randomly either, her team says. “More susceptible and more connected individuals have a higher propensity to be infected and thus are likely to become immune earlier. Due to this selective immunization by natural infection, heterogeneous populations require less infections to cross their herd immunity threshold,” they wrote.22 While most experts have taken the R0 for SARS-CoV-2 (generally estimated to be between 2 and 3) and concluded that at least 50% of people need to be immune before herd immunity is reached, Gomes and colleagues calculate the threshold at 10% to 20%.2223
(2) If the latter is so — and if you keep in mind that documented COVID19 infections are just the tip of the iceberg, with 90% of more beneath the surface — then these graphs from Sweden make some sense. (H/t: Yves not-Cohen)
Swedish public health chief Anders Tegnell, when criticized about the Swedish “Sonderweg” (special road; road alone), said “ask me again in another year”. With 88,000 documented infections out of a population of 10.23 million, they still seem far away from herd immunity — but if you assume a 10:1 to 20:1 Dunkelziffer, and if you also assume a sizable chunk of the population already has some cross-reactivity from common cold coronaviruses, then the virus may simply “be running out of easy targets”.
(1) So Israel is entering the new Jewish year with a second lockdown. The multiple “no-work” holidays in these three weeks will mitigate the economic damage somewhat, although unfortunately 1st day of Rosh Hashana and the first and last days of Sukkot all fall on a Sabbath this year.
But it is, in truth, a “lockdown lite”. Businesses that do not have storefronts accessible to the public continue operation as usual, and all “essential businesses” (food, medicine, household products, phone stores,…) remain open. Even the foodsellers in the Machane Yehuda market of Jerusalem are permitted to stay open. Restaurants and eateries are delivery only.
Theoretically, we are restricted to within 500 meter from our house. In practice, there are so many exceptions to this rule (travel to and from work, travel to and from stores selling essential products, sports activity individually or with housemates,…) that one can find an excuse. Public transportation is limited to 50% of capacity.
In my opinion, the most effective component of the lockdown is the closing of schools: I know post hoc is not propter hoc, but I doubt it is just a coincidence that we get a surge in infections a couple weeks after a school system opens or reopens (be it the state school system last May, the state school system again September 1, or the religious seminaries a month ago).
The other component may be that it will impede large family gatherings, where a child who is COVID positive (and likely has no symptoms at all or just some minimal malaise) infects grandparents who are then fighting for their lives 2 weeks later.
While the hitech sector is generally fairly resilient to the COVID-19 crisis, some niche segments are hit. WAZE (the popular crowdsourced mapping and route planning app, originally an Israeli startup, now wholly owned by Google) will be laying off people as during lockdowns it made almost no ad revenue — because people weren’t driving (or if they drove at all, not driving anywhere that they needed to open WAZE for).
All things are poison, and nothing is without poison, the dosage alone makes something not be a poison.
Paracelsus. (Original wording: Alle Dinge sind Gift, und nichts ist ohne Gift, allein die Dosis macht dass ein Ding kein Gift ist.)
I couldn’t help thinking of this when viewing Dr. Campbell’s latest video.
It also discusses a few other subjects. One is anecdotal evidence that Anthony Fauci MD is taking high doses of vitamin D supplements (as I myself have been doing at, among others, Dr. Campbell’s urging). Another is progress with vaccines: supposedly the United Arab Emirates (which, together with fellow Persian Gulf state Baḥrain, just signed the historic Abraham Accords with Israel) completed Phase 3 trials with a Chinese vaccine (an old-school attenuated-virus vaccine, not an mRNA vaccine like Oxford/AstraZeneca) and have given emergency approval for the vaccine.
But the top story is a new “perspective article” in the New England Journal of Medicine (about which ‘masgramondou’ tipped me off earlier): “Facial Masking for Covid-19 — Potential for “Variolation” as We Await a Vaccine” by Monica Gandhi, M.D., M.P.H., and George W. Rutherford, M.D.
There has been increasing evidence that the “inoculum”, i.e., the viral load of infection, determines the severity of the disease: this is not unique to COVID19, by the way, nor to viral diseases. Actually, this is the mechanism of the pre-vaccine technique known as variolation: in China and the Middle East, people would be deliberately exposed to a small amount of pus of a smallpox sufferer, thus to induce a mild case of the disease and subsequent immunity. This technique was adopted in England in 1721 by an aristocratic woman who had seen it in action during a visit to Istanbul. (True vaccination — in this case, exploiting cross-immunity with cowpox — wouldn’t be introduced by Edward Jenner until nearly 1800.)
Many people mistakenly think of infection as a binary state: either you get one or a few viral particles in and you’ll get sick and (Heaven forbid) might die. In fact, if you get in a small dose of a viral pathogen, the body’s rapid-response immune system may well eliminate it before you even have a chance to feel sick. (An RT-PCR test for the said virus’s RNA may, however, well test positive!) Think of it that way: in the pre-hitech era (say, during World War Two) if your defense lines were breached by a small force of platoon or company side, it would be quickly repelled or eliminated, while a breakthrough by a division, let alone an army corps (consisting of several divisions), would be much more of a headache.
This same “all or nothing” thinking informs much of the public thinking about masks, which particularly in the US has become nearly “tribal binary” — people tend to either fetishize them (and shame other for not wearing them, even in environments where they are really not needed) or to denigrate them on the ground that cloth or surgical masks are way too porous to block viruses. (N95 masks can stop viral droplets, but can hamper breathing if you are not used to wearing them. Several companies now offer bactericidal and viricidal masks, which I have discussed here before.)
The above-mentioned paper paints a more nuanced picture: yes, masks have value in protecting others against you (unless there is enough distance and fresh air that it is unneeded) — but they also reduce the viral load, the inoculum, should an infected person expose you, and they thus increase the chance that you will get off cheap with an asymptomatic or minimally symptomatic infection. Quoting from the article:
If the viral inoculum matters in determining the severity of SARS-CoV-2 infection, an additional hypothesized reason for wearing facial masks would be to reduce the viral inoculum to which the wearer is exposed and the subsequent clinical impact of the disease. Since masks can filter out some virus-containing droplets (with filtering capacity determined by mask type),2 masking might reduce the inoculum that an exposed person inhales. If this theory bears out, population-wide masking, with any type of mask that increases acceptability and adherence,2 might contribute to increasing the proportion of SARS-CoV-2 infections that are asymptomatic. The typical rate of asymptomatic infection with SARS-CoV-2 was estimated to be 40% by the CDC in mid-July, but asymptomatic infection rates are reported to be higher than 80% in settings with universal facial masking, which provides observational evidence for this hypothesis. Countries that have adopted population-wide masking have fared better in terms of rates of severe Covid-related illnesses and death, which, in environments with limited testing, suggests a shift from symptomatic to asymptomatic infections. Another experiment in the Syrian hamster model simulated surgical masking of the animals and showed that with simulated masking, hamsters were less likely to get infected, and if they did get infected, they either were asymptomatic or had milder symptoms than unmasked hamsters.
Israel has had a mask mandate for months now, although I can tell mask discipline is lackadaisical and people who do wear them do not do so correctly. We do have galloping apparent infection rates now — but all told, the percentage of cases that require hospitalization is quite small, about one in forty to forty-five. (That ratio has held true for a few months now.)
In fact, I strongly suspect that the high new case numbers that have prompted our imminent lockdown (we’re the first country in the world to lock down twice) are an artifact of hypersensitive RT-PCR testing at ever increasing rates: if you know from serological studies that you have a “stealth infection rate” of 10 times the documented RT-PCR, then suddenly increasing from 30,000 to 55,000 tests per day will of course turn up more cases. I roll my eyes every day about innumerate journalists (BIRM) getting all atwitter over momentary variations in daily data. (The other week, I had to explain to somebody who ought to know better what the point of a 7-day moving average was.)
Note something about the age and gender distribution of infections:
Yes, there are the “bulges” among teenagers and army and college ages, none of whom are much into social distancing in this culture. But the spike between ages 10-19 also decidedly skews male, which I suspect is related to the reopening of yeshivot (religious academies) in the chareidi (so-called “ultra-Orthodox”) sector. Still, shocking as the story of a Talmudic student in his mid-thirties (with no pre-existing conditions) dying of COVID19 may be, it is news precisely because it is an anomaly.
But what does a “case” really mean? (H/t: masgramondou.) If your body takes in a small inoculum and fights off the infection successfully without you even noticing it, does that even count as a disease, or as “Tuesday”? (Remember, quaint as this may sound, there are other viruses than COVID19 that our immune systems periodically need to get rid of an invasion in platoon or company strength of.) Yet, you will likely test positive on an RT-PCR test, and add to the kind of statistics that the media and politicians can lose their cool over (as they cannot distill the signal from the noise).
To be fair, though, I gather what ultimately swayed the decision makers, — including coronavirus czar Prof. Roni Gamzu who has been pushing back against a lockdown since his appointment — were reports that certain hospitals in Jerusalem and the North were transfering excess COVID19 patients to hospitals in the coastal plain that still had spare capacity in their COVID wards. (Such ‘load balancing’ is completely legitimate, but suggests the system is nearing its capacity limit.)
Details are still being worked out, but the closure itself has been agreed upon — despite even hospital directors being divided on the need for this. The cabinet was basically told by the health minister, Yuli Edelstein, “this is the plan, take it or leave it, I won’t prepare another”. Meeting was stormy, with Netanyahu, Edelstein, and coronavirus czar Prof. Roni Gamzu all getting lambasted. (Gamzu has been fighting a rearguard battle against full closure for as long as he’s been in the position: what swayed him this time around is not clear.)
The timing is effectively over the High Holidays (Rosh HaShana/Jewish New Year, Yom Kippur, and Sukkot). This will somewhat mitigate economic damage, as so much of the economy shuts down on these holidays anyhow. The usual pre-Rosh HaShana shopping will not be affected as the closure begins effectively on the afternoon of our weekend. Essential stores (food, medicine,…) will be exempt from the closure (as last time).
Israel has been ramping up testing capability, with about 44,000 tests per day yesterday and the day before. Considering that there are probably 10 undetected cases out there in the community for every positive case, it should surprise exactly nobody that now positive tests also have gone up, reaching a high of nearly 4,000 a day.
There is thus now a push for a renewed lockdown over the High Holidays and Sukkot. The reasoning goes that, since so much of the country’s economy is on a pilot light during these holidays, a lockdown now would be less costly from an economic point of view. Our coronavirus czar, economics professor and obstetrician Roni Gamzu (on leave as CEO of Ichilov/Sourasky Medical Center, the largest hospital in Tel-Aviv proper) has been fighting a rearguard battle against lockdown as he believes (IMHO rightly) its costs (economic as well as collateral morbidity and mortality) will outweigh its benefits.
A list of 40 “red-zone” towns and neighborhoods has been released in which an evening curfew is in force. Almost without exception, these are Arab, Druse, and Chareidi (“ultra-Orthodox”) communities, which between them account for the majority of new cases. This has been linked to mass weddings in the Arab sector (it being the wedding season there now, and ‘personal space’ being a novel concept in this part of the world), as well as to the reopening of yeshivot (Talmudic academies), traditionally one month before Rosh HaShana. In the secular and national-religious Jewish sectors, schools have reopened since September 1.
Today I saw an interview on Channel 12 news with another opponent of lockdown — none other than the director of emergency medicine at Laniado Hospital in Netanya, Dr. Amir Shachar.
he is one of the founding fathers of modern emergency medicine[*] in Israel; over 30 years ago, he set up the new emergency department at Sheiba/Tel HaShomer hospital and ran it for many years, before leaving for a position with the Shin Bet (Israel’s domestic intelligence agency). After surviving a bout with leukemia, two years ago he came out of retirement to lead the emergency department at Laniado
He is thus in the COVID19 frontline now, despite being in a risk group himself
His view is that yes, COVID19 is a serious disease, but one with which we will need to learn to live at least for some time — not shut the planet down
Collapses of the medical systems in Spain and Italy in the first any wave resulted from mismanagement of said systems, not from objective medical factor. They triggered a first wave of lockdowns that was, with hindsight, unnecessary
“decision makers then were not medical professionals” — he mentions former health ministry director-general Moshe Bar-Siman Tov by name, a seasoned bureaucrat who came from the Finance Ministry without any medical background. (Don’t get me started on the minister.) “Then you get idiocy like racing to get 3,000 ventilators which turned out to be completely unneeded.”
“In the future, people will look back on how we responded in 2020 and shake their heads”
the number of “severe cases” is inflated because of changes in the criteria for classification. “A patient with a pO2 [blood oxygen saturation level] of 93% was ‘mild’ until July 12, when they suddenly became ‘severe’ — even if they need nothing [he means: oxygen, respirator,…]”
the average age of COVID19 deaths is 81, the majority with multiple pre-existing conditions
“people age 90 or 100 die, not because of COVID19, but because they have [any] disease [at all]”
“the second wave” should really be called “the testing plague” (his term: magefat ha-bedikot). “We go into a panic because we test so much. If we didn’t, then the serious cases would show up anyhow, and the rest would get over it and develop immunity.”
the hospital’s director, Dr. Nadav Chen, adds remark about another plague: chronic shortness of financial breath. “We haven’t been able to pay our suppliers for PPE they rushed to us during the first wave. Now they’re out on the streets demonstrating because they are going under.”
In this context should be seen Dr. Shachar’s earlier remark that hospitals are dramatizing and exaggerating the degree of COVID19 burden as a means of getting financial relief. (And no, he is not suggesting the hospitals need that to pay for frivolities.)
A New York Timesarticle entitled Your Coronavirus Test Is Positive. Maybe It Shouldn’t Be, said: “The PCR test amplifies genetic matter from the virus in cycles; the fewer cycles required, the greater the amount of virus, or viral load, in the sample. The greater the viral load, the more likely the patient is to be contagious. […] This number of amplification cycles needed to find the virus, called the cycle threshold, is never included in the results sent to doctors and coronavirus patients, although it could tell them how infectious the patients are. In three sets of testing data that include cycle thresholds, compiled by officials in Massachusetts, New York and Nevada, up to 90 percent of people testing positive carried barely any virus, a review by The Times found.”
Channel 12 News reported that while Germany uses 30 amplification cycles, Singapore 32, and the United States 34, Israel uses up to a full 37 amplification cycles to detect viral genetic matter. Many experts agree that anything higher than 30 amplification cycles will result in inactive, dead, or clinically insignificant amounts of the virus being detected, therefore causing the test to show as positive.
[…] Shahar spoke with Sivan Cohen and explained why he felt the Swedish method of fighting the virus should be adopted, expressing his opinion on the expected closure: “It’s an epidemic but it harms the weak, the sick, and the elderly. The virus does not pose a threat to society.” He went on to comment on the high coronavirus data and corrected: “We only have about 50 new [actual] patients in Israel a day, and not 3,000. The health system should be given the means to cope long-term.” “Most of the people identified as carriers are not sick, or they are very lightly ill, and I’m trying to say that this figure of 3,000 or 4,000 new patients a day is simply using wrong definitions. There is no disease that is diagnosed by identifying the contagion in the throat. There also need to be symptoms and most of the people identified as positive and get the label ‘sick’ are not sick.” The interviewer answered Dr. Shachar, “They’re carriers…” “They’re not even carriers,” answered Dr. Shachar, “They’re people who were exposed to the virus. Hundreds of viruses pass our way every day.”
Controversial words, for sure. But not those of a conspiracy nut or political hack, but of a veteran, respected medical professional. Food for serious thought.
[*] as distinct from trauma/battlefield medicine, with which this country sadly acquired ample experience.
(1) Israel, where I live, has crossed a grim milestone: total cumulative deaths exceed 1,000 for the first time. Of course, countries like Belgium would say “we should be so lucky”. But remember that Israel’s criteria for coding a death as COVID19 are fairly strict: you can assume nearly every one of these died of and not just with the disease. We currently have a rampant infection rate, although the case fatality rate is kept low by our “young” population pyramid
plus new infections being disproportionately in the below-30 age brackets
I am the last person to make light of this epidemic, but 0.01% in fact means you have a higher risk of being killed in a car accident (lifetime odds: 0.94%) than of COVID19. There was a story the other week about Americans in their thirties thinking they had a 10-20% chance of dying of Corona if they got it. (Sigh of cosmic weariness/un soupir de lassitude cosmique/zucht van eindeloze vermoeidheid/ein Seufzer endloser Ermüdung.)
In Israel too, deaths are primarily among the elderly. The following infographic is for all deaths in the month of July: only 3 out of 210 were under 50
and 85% were age 70 or over, 60% age 80 or over. Via the Hebrew news media, I heard our oldest death with COVID19 was age 102. A patient age 19 with multiple underlying conditions represents the youngest.
I should point out Israel has had a mask mandate for months, and yet it has one of the highest per capita infection rates now. People honestly don’t know how to wear them, and it may actually be that they give people a false sense of security and a false sense of freedom to flout other aspects of social distancing— in particular, the concept of personal space is a novel notion in the Middle East, and this has not improved much during the epidemic. (When making comparisons with the USA, please do keep in mind that this country is very densely populated: for instance, the ‘suburbs’ of Tel-Aviv I live in has the same population density as downtown Chicago.)
(1) The claim that “only 6% of COVID deaths are really COVID”. He uses the non-COVID example of a diabetic who dies of septic shock after he gets a cut on his arm and develops necrotizing fasciitis (“flesh-eating bacteria”), then when antibiotics fail to stop the infection goes into septic shock, renal failure, and cardiac arrest. What is the proximate/immediate of death? What are the contributory causes? What is the root/underlying cause of death? He shows an example death certificate: in this case, the immediate cause is ARDS (caused by COVID19 pneumonia), and the underlying cause (listed at the bottom) is COVID19. Pneumonia and ARDS are not “comorbidities” as the term is medically understood; if the patient had, e.g., also cancer and diabetes type 2, those would be comorbidities.
This is not to say that there haven’t been abuses of the system, like logging deaths from gunshot wounds as COVID19. Nor is it to deny that the public health authorities in especially the US have squandering public trust and goodwill by poor communication, lack of transparency, and by blatantly placing political expedience before public health.
But if mortality were really only 6%, then excess deaths would only show as a small blip compared to the average over the past several years. (And this is, indeed, how the COVID19 mortality in Belgium was revealed to be inflated.) But as Dr. Seheult shows, in the USA excess deaths are higher than what can be accounted for through COVID19: I suspect the difference is collateral damage from the deferral of care for diseases other than COVID19. (Wisely, medical systems in countries like Germany and Israel never went into “COVID19 only mode”.)
Panic is a poor guide in a public health crisis, but so is wishful thinking.
considers high doses of calcifediol (a vitamin D metabolite given to people who have trouble absorbing actual vitamin D) vs. only standard of care for hospitalized COVID19 patients. (Interestingly, the local standard of care included hydroxychloroquine and azithromycin:
Procedures All hospitalized patients received as best available therapy the same standard care, (per hospital protocol), of a combination of hydroxychloroquine (400 mg every 12 hours on the first day, and 200 mg every 12 hours for the following 5 days), azithromycin (500 mg orally for 5 days. Eligible patients were allocated at a 2 calcifediol:1 no calcifediol ratio through electronic randomization on the day of admission to take oral calcifediol (0.532 mg), or not. Patients in the calcifediol treatment group continued with oral calcifediol (0.266 mg) on day 3 and 7, and then weekly[…]
) From the Results section of the abstract:
Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50%) p value X2 Fischer test p<0.001. Univariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment versus without Calcifediol treatment: 0.02 (95%CI 0.002-0.17). Multivariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment vs Without Calcifediol treatment ICU (adjusting by Hypertension and T2DM): 0.03 (95%CI: 0.003- 0.25). Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged.
(1) In this video, Dr. Seheult briefly discusses three treatments that got EUA (emergency use authorization) from the FDA: remdesivir, dexamethasone, and convalescent plasma. He discusses his own clinical experiences treating patients with the first two (and promises a future update about convalescent plasma). He stresses that, while we may know from science what drugs may work, the key when treating actual patients is to watch and monitor them carefully. For example (it seems obvious in retrospect), a patient on the ventilator may be breathing very rapidly, and dissipate a lot of water vapor breathing out; this may lead to dehydration, a rise in Na+ levels,… unless compensated for by IV.
(3) A brief situation update from Israel. We continue to have as many as 2,000 new confirmed infections per day, and sadly our deaths are creeping towards the 1,000 mark. We have 845 COVID19 patients in hospital, of which 159 in moderate and 422 in severe condition, with 127 of the latter on respirators. (The “missing” 264 patients are presumably mild COVID19 cases actually hospitalized for something else.) Nearly 22,000 mild or asymptomatic cases are either at home or — if isolation at home is not feasible — in “coronahotels” about which I’ve blogged.
The good news: our case fatality rate is way down from the first wave. If we take May 25, with just 13 new cases (after that comes a steady increase), as the cutoff point between waves, we get a fatality rate of 281 deaths out of 16,734 verified infections=1.68%. From then until September 1, inclusive, we’ve accumulated another 101,804 verified infections and 676 deaths, which works out to a fatality rate of just 0.664% for the second wave.
While Israel tests fairly aggressively (as many as 36,000 in one day), serological testing still indicates an appreciable Dunkelziffer (infected “dark matter”) — as of early June, about 10:1. If this ratio (which is lower than what serological studies elsewhere have indicated) holds true, then as many as 1.2 million Israelis out of 8.67 million, or just shy of 14%, have been infected. That seems far from herd immunity, but not as far as people may think: consider the revised version of the higher-order herd immunity paper https://arxiv.org/abs/2005.04704v2,now retitled “Heterogeneity in susceptibility dictates the order of epidemiological models”.