COVID19 update June 3, 2020: serological study in Israel; Surgisphere data scandal [UPDATED]

(1)  Israel is planning to test a sample of 70,000 people for antibodies. Earlier, preliminary result from a smallish sample of 1,709 Israelis found that 2.5±0.5% had antibodies for the virus. With official infection numbers (positive tests in RT-PCR) reaching only 0.2% of the population, this implies a Dunkelziffer  (stealth infection rate) of 10-15 times the official one — not dissimilar from what Prof. Hendrik Streeck found in Germany or the team of Ioannides, Bendavid et al. found in Santa Clara County, CA. [For non-American readers: Santa Clara County is almost synonymous with Silicon Valley.] 

With just 291 dead out of 17,377 confirmed cases — a raw case fatality rate (CFR) of 1.67%, this implies that the infection fatality rate is just 0.11–0.17%. This is considerably lower than even the drastically downward-revised CDC figures,  (IFR of about 0.26%), but Israel has a much younger population pyramid than the USA, and is sunny enough that vitamin D deficiency should not be as prevalent as in  northern US states.

Meanwhile, Israel is seeing a flare-up of cases in schools that has some people speaking of a second wave, although it might actually be more like a ripple, or a round of the dance in Tomas Pueyo’s “Hammer and Dance” strategy. Rungholt blogs in German about her experience as a kindergarten teacher in a kibbutz in the far North of the country.

(2) h/t: Cathe Smith: several papers, including the one that led to suspension of the hydroxychloroquine trials, now under a cloud owing to suspect medical database

On its face, it was a major finding: Antimalarial drugs touted by the White House as possible COVID-19 treatments looked to be not just ineffective, but downright deadly. A study published on 22 May in The Lancet used hospital records procured by a little-known data analytics company called Surgisphere to conclude that coronavirus patients taking chloroquine or hydroxychloroquine were more likely to show an irregular heart rhythm—a known side effect thought to be rare—and were more likely to die in the hospital.

Within days, some large randomized trials of the drugs—the type that might prove or disprove the retrospective study’s analysis—screeched to a halt. Solidarity, the World Health Organization’s (WHO’s) megatrial of potential COVID-19 treatments, paused recruitment into its hydroxychloroquine arm, for example. (Update: At a briefing on 3 June WHO announced it would resume that arm of the study.)

But just as quickly, the Lancet results have begun to unravel—and Surgisphere, which provided patient data for two other high-profile COVID-19 papers, has come under withering online scrutiny from researchers and amateur sleuths. They have pointed out many red flags in the Lancet paper, including the astonishing number of patients involved and details about their demographics and prescribed dosing that seem implausible. “It began to stretch and stretch and stretch credulity,” says Nicholas White, a malaria researcher at Mahidol University in Bangkok.

Today, The Lancet issued an Expression of Concern (EOC) saying “important scientific questions have been raised about data” in the paper and noting that “an independent audit of the provenance and validity of the data has been commissioned by the authors not affiliated with Surgisphere and is ongoing, with results expected very shortly.”

Hours earlier, The New England Journal of Medicine (NEJM) issued its own EOC about a second study using Surgisphere data, published on 1 May. The paper reported that taking certain blood pressure drugs including angiotensin-converting enzyme (ACE) inhibitors didn’t appear to increase the risk of death among COVID-19 patients, as some researchers had suggested. (Several studies analyzing other groups of COVID-19 patients support the NEJM results.) “Recently, substantive concerns have been raised about the quality of the information in that database,” an NEJM statement noted. “We have asked the authors to provide evidence that the data are reliable.”

A third COVID-19 study using Surgisphere data has also drawn fire. In a preprint first posted in early April, Surgisphere founder and CEO Sapan Desai and co-authors conclude that ivermectin, an antiparasitic drug, dramatically reduced mortality in COVID-19 patients. In Latin America, where ivermectin is widely available, that study has led government officials to authorize the drug—although with precautions—creating a surge in demand in several countries.

Chicago-based Surgisphere has not publicly released the data underlying the studies, but today Desai told Science through a spokesperson that he was “arranging a nondisclosure agreement that will provide the authors of the NEJM paper with the data access requested by NEJM.”

UPDATE (h/t LIssa Hailey): much more at The Guardian (archive copy here) “Governments and WHO changed Covid-19 policy based on suspect data from tiny US company”

A search of publicly available material suggests several of Surgisphere’s employees have little or no data or scientific background. An employee listed as a science editor appears to be a science fiction author and fantasy artist. Another employee listed as a marketing executive is an adult model and events hostess.

[…] Until Monday, the “get in touch” link on Surgisphere’s homepage redirected to a WordPress template for a cryptocurrency website, raising questions about how hospitals could easily contact the company to join its database.

[…] At a press conference on Wednesday, the WHO announced it would now resume its global trial of hydroxychloroquine, after its data safety monitoring committee found there was no increased risk of death for Covid patients taking it.

The article refers to an earlier expose at MedicineUncensored.

COVID19 update, May 28, 2020: ACE inhibitors beneficial; asymptomatic infection rate as high as 80%; NYT on California economy in freefall

(1) The lead story of Chemical and Engineering News, the house organ of the American Chemical Society, is about rethinking the role of ACE inhibitors (angiotensin converting enzyme inhibitors, a commonly used family of blood pressure drugs).

https://cendigitalmagazine.acs.org/2020/05/22/rethinking-the-role-of-blood-pressure-drugs-in-covid-19/content.html

“Once thought to boost levels of ACE2 , the novel coronavirus’s doorway into human cells, these widely used medicines are now contenders to treat the respiratory disease”

(2) Meanwhile,  the Daily Telegraph has a popular write-up of an intriguing paper that just appeared in Thorax, a daughter journal of the British Medical Journal. It suggests the asymptomatic infection rate may be much higher than the 35% in the revised CDC figures

http://doi.org/10.1136/thoraxjnl-2020-215091

ABSTRACT: We describe what we believe is the first instance of complete COVID-19 testing of all passengers and crew on an isolated cruise ship during the current COVID-19 pandemic. Of the 217 passengers and crew on board, 128 tested positive for COVID-19 on reverse transcription–PCR (59%). Of the COVID-19-positive patients, 19% (24) were symptomatic; 6.2% (8) required medical evacuation; 3.1% (4) were intubated and ventilated; and the mortality was 0.8% (1). The majority of COVID-19-positive patients were asymptomatic (81%, 104 patients). We conclude that the prevalence of COVID-19 on affected cruise ships is likely to be significantly underestimated, and strategies are needed to assess and monitor all passengers to prevent community transmission after disembarkation.

The Uruguayan Ministry of Health provided on board SARS-CoV-2 virus testing of all passengers and crew, which occurred on 3 April (day 20; Atgen-Diagnostica, Montevideo) with CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel.

In the body text we find that: 

 

[The 128 who tested positive on RT-PCR]  included all passengers who tested negative on the VivaDiag qSARS-CoV-IgM/IgG Rapid [antibody] Test. There were 10 instances where two passengers sharing a cabin recorded positive and negative results.

[…]

From the departure date in mid-March 2020 and for the next 28 days, the expedition cruise ship had no outside human contact and was thus a totally isolated environment in this sense. […]

[…]

We conclude from this observational study that

  • The prevalence of COVID-19 on affected cruise ships is likely to be significantly underestimated, and strategies are needed to assess and monitor all passengers to prevent community transmission after disembarkation.
  • Rapid  [antibody] COVID-19 testing of patients in the acute phase is unreliable.
  • The majority of COVID-19-positive patients were asymptomatic (81%).
  • The presence of discordant COVID-19 results in numerous cabins suggests that there may be a significant false-negative rate with RT-PCR testing. Follow-up testing is being performed to determine this.
  • The timing of symptoms in some passengers (day 24) suggests that there may have been cross contamination after cabin isolation.

 

Just how reliable is RT-PCR really?  According to this piece in IEEE Spectrum, current test setups reach are essentially 100% sensitive (no false negatives) and 96% specific (4% false positives) with lab-generated samples., i.e., if you feed them virus cultures. The trouble begins when you have to collect specimens from actual patients.  According to this piece in MD Magazine,   “Of the specimens collected [from known COVID-19 patients], bronchoalveolar lavage fluid specimens demonstrated the highest positive rates of at 93% (n = 14). This was followed by sputum at 72% (n = 75), nasal swabs at 63% (n = 5), fibrobronchoscope brush biopsy at 46% (6/13), pharyngeal swabs at 32% (n = 126), feces at 29% (n = 44) and blood at 1% (n = 3). The authors of that study pointed out that testing of specimens from multiple sites may improve the sensitivity and reduce false-negative test results.” 

 

(3) Via David Bernstein: the WSJ on New York’s long road to recovery even after a lifting of the lockdown. (Archived copy here.)

And via Instapundit, the NYTimes on The price of a lockdown: economic freefall in California

(archived copy ) To be fair, the tourism industry would have been bludgeoned with or without a lockdown, as the (proportionally less important) Swedish tourism sector has learned.

But a large part of the rest could have been mitigated, and can still be mitigated, by not going the “37-step reopening over 10 years” route in California.  (Heck, when did The Babylon Bee forget it was a satirical publication?) But — as much as this sickens even the jaded student of history — I suspect that for some politicians, ensuring that the recovery does not happen before November is worth any price…  

 

Finally, to my Jewish readers, happy Shavuot! There will probably not be an edition on the holiday unless breaking developments warrant it.

 

ADDENDUM: an op-ed in The Lancet in defense of prophylactic use of hydroxychloroquine in India.

COVID19 update, April 19, 2020: Israel reopens; NYC vs. rest of USA; quick takes

(1) Today, Israel started Phase 1 of its “back to normality” plan. There appears to have been intense tug-of-war between economic and healthcare decision makers, which resulted in some tradeoffs. Masks were made mandatory, giving in to a strong demand from the Health Ministry, but in compensation, a large number of retail stores that were only supposed to reopen in Phase 2 are doing so right now.

I treated myself to a long walk around the Tel Aviv borough where I live. About 2 in every 3 stores was open for business, and of the remainder, some were setting up for reopening.

(2) Matt Margolis enters into the differences between NYC and the rest of the USA as far as COVID19 is concerned.

The numbers are shocking. Downstate has been so heavily impacted by the coronavirus that it skews the United States when you compare us to the rest of the world.

Downstate New York technically includes New York City, Long Island, and the Hudson Valley, but I am only including Kings, Queens, New York, Suffolk, Bronx, Nassau, Westchester and Richmond Counties. These counties have a population of 12,205,796, according to World Population Review’s numbers for 2020—bigger than many countries.

It’s currently claimed that the USA “leads the world in COVID19 cases and deaths”. In fact, as Matt points out, in confirmed cases per capita, the US is only #7 worldwide (Spain is #1). Bad enough, you say? But if we treated greater NYC/”downstate New York” as a separate country, it would have #1 worldwide by a longshot — with four times the per capita incidence of Spain at #2. “USA minus NYC” would only be #14 worldwide. In per capita fatality rates, the whole USA comes at #8 [I suspect actually as #9, since Sweden appears to be omitted in that list], but NYC treated as a country would again be the #1 by far, with double the mortality of the #2 (Belgium). “USA minus NYC” drops to #11.

(3) Germany apparently is starting broader community testing for antibodies. On a related note (via Instapundit), physicians from Mass General Hospital tested 200 random people in the marketplace of Chelsea, MA, and found that 1/3 had antibodies for COVID.

(4) The Great Decoupling? Legal Insurrection reviews worldwide signs of countries “socially distancing” from the Chinese communist regime. Even Emmanuel Macron [!] now seems to get it.

(5) The German tabloid BILD reports on successful use of Remdesivir in Munich. With every new report, I’m getting more positive about that drug.

(6) Prof. Jonathan Gershoni of Tel-Aviv U. claims to be “2/3 of the way toward a vaccine”. The basic idea of most vaccine developers seems to be to target the “spikes” of the coronavirus, which are responsible for getting cells to let the virus in. If the virus were to lose those in a mutation-evolution process in an attempt to ‘get around the vaccine’, it would become a lot less dangerous anyhow.

(7) And it appears that some applied mathematicians who noticed a repeated empirical pattern in the progress of the epidemic in several countries may have rediscovered Farr’s Law.

COVID19 update, April 14, 2020: vitamin D, zinc, testing; end of globalization as we know it?

(1) Roger Seheult MD in his latest update gives a clear discussion of RT-PCR (reverse transcriptase polymerase chain reaction) testing vs. antibody testing.

I spoke to an industry insider about why not more antibody testing yet? I was told that first-generation antibody testing kits achieved accuracies of around 30%, which are “worse than useless”. But accuracies are steadily improving, and we should soon be looking at something comparable in accuracy to a good RT-PCR.

In response to reader demand, Dr. Seheult also gives a link to a hydrotherapy regime that might be useful for prophylaxis and for treatment of mild cases — but only in addition to more conventional approaches: https://www.hydro4covid.com

(2) Nursing school instructor John Campbell, in his latest update, hammers a lot on the beneficial effect of vitamin D for the human immune system. In fact, he looks at the different mortality statistics for ethnic groups in NYC, and finds it fascinating that everybody comes up with socio-economic explanations while overlooking something obvious: at northern latitudes, vitamin D deficiency is quite common among dark-skinned people. (In fact, both the white and “yellow” skin types evolutionarily started as mutations that just happened to allow humans to thrive in less-sunny northern regions.)

He strongly recommends everybody who does not already enjoy abundant sunshine take vitamin D supplements to boost their immune systems — especially people with darker skin types.

On a related note, he looks at the surprisingly mild statistics of the epidemic in Australia, and notes that this militates in favor of seasonality — but again stresses the beneficial effect of vitamin D in the sunny Australian summer and early fall. (I note that South Africa too has so far dodged a major bullet.)

He also notes that homes for the elderly everywhere have appalling statistics — it takes only one or two cases to cause a major outbreak in one unless you really know what you are doing.

One more thing: out of 459 newly diagnosed cases in South Korea, 228 are imports from the USA. While he admits this will not be a representative sample of the US population (whoever still travels may be a businessman or some sort of expert), it does have implications for the Dunkelziffer/”dark case load” in the USA.

(3) Speaking of nutrition, a number of doctors advocate zinc supplements. [Full disclosure: I have been taking such since the beginning of the crisis.] This is emphatically not quack science: zinc is an essential nutrient, and in fact the most common transition metal in the body outside the bloodstream. (Iron in hemoglobin is the most common one if you include it.) Hundreds of physiological processes depend on zinc in the catalytic site of an enzyme, as a co-catalyst or modulator, or as a structural element. This includes the immune system too: I was struck between the similarity between some early COVID19 symptoms (such as loss of taste and smell) and those of zinc deficiency (presumably because Zn is mobilized in great amounts for the immune system). Here is an academic review article on the roles of zinc in the antiviral immune system.

Particularly people who live on vegetarian diets are at risk for Zn deficiency — those who primarily live on red meats or seafood least so.

(4) Urban geographer Joel Kotkin, in a must-read essay , explains how COVID19 (and whatever similar epidemics may lay in our future) will make dense urban centers less attractive to live in. He notes NYC accounts for nearly half of COVID19 mortality in the USA, greater Milan for half the cases in Italy and almost 3/5 of deaths,… “Simply put, pandemics are bad for dense urban areas, particularly those that are diverse and relatively free. This has been very much the case since antiquity. The more global and vital an urban system—Rome, Alexandria, Cairo, Venice, Florence, London, Paris—the more susceptible it is to the pandemics that seem to be occurring regularly over the past two decades. Cities no doubt will recover, particularly if real estate prices continue to fall, but the pandemics limit their upward trajectory and will continue to drive people elsewhere.”

On a related note, former director of the World Bank’s research department Branko Milanovic, https://www.standaard.be/cnt/dmf20200327_04904960 interviewed in De Standaard (in Dutch) argues that (my paraphrase) “We went for the extremes of globalization because technology enabled it. COVID19 showed such an economy is brittle.” He does see a return to some form of globalized economy the day after the crisis, but not again to this extreme extent.

It is noteworthy that such “the end of globalization as we know it” rhetoric is not the province of just the American populist “right”, but that one can hear similar voices around the globe and the political spectrum from the German establishment center-right to the left. I was (pleasantly) surprised to read a scathing article in The Guardian (!!) about the way some Chinese academic publications about the origins of the virus had to be airbrushed by CCP regime fiat. “Oceania is not at war with Eurasia.” [On a related note, Taiwan released an Email from December in which it warned the WHO about patients with a new, SARS-like lung disease.]

The American Interest looks at the long, hard road to decoupling from China. An article in De Standaard (in Dutch) entitled “[shoddy m]asks as a canary in the coalmine”, looks at the trend towards what it calls with an English neologism “reshoring” — bringing production back home to have better control over supply chain and especially quality. This process is said to have been going on for a while in Belgium, but is now being accelerated by COVID19.

Finally, feelgood story of the day: at age 107, a Dutch woman named Cornelia Ras is now the oldest person to survive a bout with COVID19 .

COVID19 update, March 26, 2020: antibody testing could be a game changer

Multiple reports are coming in about new tests for SARS-nCoV-2 antibodies being developed and rushed into production:

• USA: Reuters dispatch

• From Belgium, De Standaard (in Dutch) reports on a homegrown antibody test that gives results in 15 minutes

• The UK is days away from rolling out “millions” of a similar test, developed at Oxford University, reports the Sydney Morning Herald.

Why is this a big deal? For one, antibody tests are way faster and easier to administer than the slow PCR testing for the virus itself. This is something that can be scaled up to entire populations of a region.

For another, if this confirms the theory of an Oxford epidemiologist that a substantial percentage of the UK population is already immune to the virus… That would completely transform the economic calculus. People who are immune could simply get tested, get a clean bill of health, and go back to work. This would go a long way to mitigating the economic damage (which ultimately filters down to everybody) of a prolonged lockdown.

Developing…

UPDATE: The New Scientist (UK popular science magazine) reports that Neil Ferguson, the Imperial College modeler whose worst-case scenario predicted two million dead in the US and half a million dead in the UK alone has now drastically revised his predictions, as evidence accumulated that the virus was both spreading more rapidly (with R0 ≈ 3). and had a lower IFR (infection fatality rate) than was originally assumed.

He said that expected increases in National Health Service capacity and ongoing restrictions to people’s movements make him “reasonably confident” the health service can cope when the predicted peak of the epidemic arrives in two or three weeks. UK deaths from the disease are now unlikely to exceed 20,000, he said, and could be much lower.

The need for intensive care beds will get very close to capacity in some areas, but won’t be breached at a national level, said Ferguson. The projections are based on computer simulations of the virus spreading, which take into account the properties of the virus, the reduced transmission between people asked to stay at home and the capacity of hospitals, particularly intensive care units.

[…]

He is also quoted in the same article that “community testing and contact tracing wasn’t included as a possible strategy in the original modelling because not enough tests were available,” but that the UK should have the testing capacity “within a few weeks” to copy what South Korea has done and aggressively test and trace the general population.


(h/t Erik Wingren). Related article.

UPDATE 2: Dr. Deborah Birx, WH Coronavirus Response Coordinator, weighs in on the drastic downward revision