COVID19 update, June 27, 2020: The Economist on how COVID-19 changed the office; reduced hospital fatality rates in the UK; initial infection rates may have been 80 times higher than reported

(1) The Economist has a video on how COVID-19 is changing the office building as we know it. Working from home used to be the exception — companies insisted that you show up in the office even for work that can be done from home very well

Now COVID-19 has forced companies to make a virtue of necessity — and it turns out this works pretty well. The video claims that 47% of all existing jobs in Switzerland can be done from home, with somewhat lower percentages for other developed economies, but much lower percentages for developing countries.

And guess what: considering how expensive office space in premium locations is (downtown Hong Kong, with about $250/mo/square meter, probably takes the case), companies can save a ton of money by letting WFH-feasible jobs be done from home and downsizing their office locations.

This will have a ripple effect: a WSJ journalist interviewed in the video claims that every Manhattan office job created employment for 5 people in the service industry (bars and restaurants, custodial,…) 

Of course, one man’s meat is another man’s poison, so it is quite possible that the lost jobs catering to downtown office worker may be partly or even wholly offset by other jobs created elsewhere — as people working from home will want to upgrade their housing arrangements, or will have more disposable income to spend on family amenities.

I would not say that COVID-19 will bring the end of the Dilbert cube farm as we know it: simply that it triggered a transformation that was waiting to happen, only delayed by managerial inertia.

(2) There are reports from various countries that hospital mortality rates have dropped considerably from the peak of the infection. The Daily Telegraph reports that mortality of COVID19 patients admitted to English hospitals has dropped fourfold, from 6% in April (the peak of the epidemic there) to 1.5% now. A number of explanations are proffered:

• Doctors have gotten better at managing the disease and mitigating its severity
• Hospitals have enough capacity now that milder cases can now be admitted that would have been sent home earlier: as these mild cases almost invariably recover, this drives down the statistics
• The most vulnerable older people either have already died or recovered, or we have simply gotten better at shielding the elderly from infection. 
• [not in the article] the better, sunnier weather reduces vitamin D deficiency

(2b) [Hat tip: Erik W.]

An epidemiological study from Penn State U. suggests that the initial COVID19 infection rate in the US may have been about 80 times the officially reported one. The paper can be read directly here:

http://doi.org/10.1126/scitranslmed.abc1126

Quoting from the abstract:

Detection of SARS-CoV-2 infections to date has relied heavily on RT-PCR testing. However, limited test availability, high false-negative rates, and the existence of asymptomatic or sub-clinical infections have resulted in an under-counting of the true prevalence of SARS-CoV-2. Here, we show how influenza-like illness (ILI) outpatient surveillance data can be used to estimate the prevalence of SARS-CoV-2. We found a surge of non-influenza ILI above the seasonal average in March 2020 and showed that this surge correlated with COVID-19 case counts across states. If 1/3 of patients infected with SARS-CoV-2 in the US sought care, this ILI surge would have corresponded to more than 8.7 million new SARS-CoV-2 infections across the US during the three-week period from March 8 to March 28, 2020. Combining excess ILI counts with the date of onset of community transmission in the US, we also show that the early epidemic in the US was unlikely to have been doubling slower than every 4 days. Together these results suggest a conceptual model for the COVID-19 epidemic in the US characterized by rapid spread across the US with over 80% infected patients remaining undetected.

Note that a “Dunkelziffer” of 80:1 is in the 50:1  – 85:1 range the [much-maligned] original version of the Santa Clara serological study (Ioannides et al.) had.

(3) “Covid toes” may actually not be a COVID-19 symptom or sequel after all, but simply result from lack of physical activity , reports UPI.

The “symptom” mirrors that of a condition called Chilblains, or perniosis, a painful inflammation of the small blood vessels in the skin that occurs after repeated exposure to cold air, they said.

(4) [Hat tip: Jeff Duntemann] A retired anesthesiologist on masks:

To protect yourself, you need an N95 respirator mask that is properly fitted.  Then you need to re-sterilize it every four hours using UV light or properly dispose of it and start over with a new one.  That is too expensive for most people.

The outside world is the safest place you can be.  The state of Florida has zero cases of COVID-19 that can be traced to outside transmission.  During the day, solar UV kills all viruses very quickly, and there’s always enough air movement to disperse aerosols, making them non-infective.  It has become clear that virtually all cases have been spread in closed spaces with prolonged (>10 minute) exposure.  And as the studies I’ve cited show, other than N95s, masks are no help there.  For that matter, six-foot spacing doesn’t help, either, since the aerosols that transmit the virus aren’t adequately dispersed.

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 23, 2020: CDC dramatically revises fatality rates downward; important new immunity data and “cross-reactivity”

 

(1) Pardon my French, but this is a big [bleep]ing deal. Via Matt Margolis, here are revised CDC best estimates for COVID-19 epidemiological parameters (Table 1, “Scenario 5”). Parameter values are based on data received by CDC prior to 4/29/2020

Their R0=2.5 (remember, R-naught is the reproductive number absent any intervention). Percent asymptotic infections is 35%. 

Age cohort  Fatality  Hospit.  of which ICU 

Under 50    0.05%     1.7%       21.9%    

50-64        0.2%     4.5%       29.2%

Over 65      1.3%     7.4%       26.8%

Overall      0.4%     3.4%       N/A 

Also according to the report, about three-quarter of patients in the ICU need mechanical ventilation of some sort, regardless of age group.

Now wait a second, you say. According to worldometers, the cumulative documented infections on April 29 were 1,064,194, with 61,655 deaths. That’s an overt case fatality rate (CFR) of 5.79% — while now CDC is talking a CFR of 0.4% CFR, and an infection fatality rate of 0.26% [that is, 0.4%*(100%-35%)]. How come?

Well, “overt” or “documented” is the operative word here. These number imply a Dunkelziffer/undocumented infection rate of about 22 times the known infection rate. (This ratio is actually within the uncertainty band of the revised Santa Clara County community sampling study. (Bendavid, Ioannides et al. from Stanford).

As I reported here on May 5, German virologist Hendrik Streeck, from his whole-community testing of the hard-hit German town of Gangelt, inferred an IFR of “0.36%, but possibly as low as 0.24%”. He at the time suggested the ratio between the overt CFR and 0.36% as a guesstimate for the Dunkelziffer. It increasingly looks like Streeck, Ioannides, and the CDC are all on the same page to within overlapping uncertainties.

 

Back in March, the single biggest “known unknown” the decision makers had was precisely the Dunkelziffer. Would they have decided on hard lockdowns based on a 0.26% IFR? Chances are, many countries would have hewn a course closer to Sweden’s. But decisions made “in the fog of war”, as a member of our local ad hoc planning commission described it, are easy to second-guess with 20:20 hindsight. Back then, our own commission applied case fatality rates by age cohort reported from China to our much “younger” population pyramid, and arrived at an “if we do nothing” back-of-envelope upper limit 20,000 dead before herd immunity would be reached. Based on  what we know with benefit of hindsight, it would probably have been more in the 3,000-8,000 range. As of today, after a strict but comparatively brief lockdown and a phased reopening, we have fewer than 300 dead out of a population of 9.15 million. So it is possible that the lockdown saved thousands of lives here — but it could be that our thankfully small mortality is thanks as much to our sunny climate and comparatively outdoors lifestyle as to any human intervention.

What we can tell now, however, is that extended lockdowns have long outlived any epidemiological purpose they ever might have had. At this point, their collateral mortality will well exceed any residual epidemiological benefit they might still have. Besides, in the states and countries that have reopened, the sky isn’t falling.

(2) This new paper in the top-tier journal CELL https://doi.org/10.1016/j.cell.2020.05.015 (h/t: LittleOldLady) and this press release about it, in layperson-friendly languagee (h/t: Jeff Duntemann) have some very hopeful  news about COVID19 and immunity. But the big shocker to me was buried further down:

The teams also looked at the T cell response in blood samples that had been collected between 2015 and 2018, before SARS-CoV-2 started circulating. Many of these individuals had significant T cell reactivity against SARS-CoV-2, although they had never been exposed to SARS-CoV-2. But everybody has almost certainly seen at least three of the four common cold coronaviruses, which could explain the observed crossreactivity.

It is still unclear, though, whether the observed crossreactivity provides at least some level of preexisting immunity to SARS-CoV-2 and therefore could explain why some people or geographical locations are hit harder by COVID-19.

“Given the severity of the ongoing COVID-19 pandemic, any degree of cross-reactive coronavirus immunity could have a very substantial impact on the overall course of the pandemic and is a key detail to consider for epidemiologists as they try to scope out how severely COVID-19 will affect communities in the coming months,” says Crotty.

 

Most common colds are caused by rhinoviruses, but actual coronaviruses account for a minority of them. “Cross-reactivity” is immunology-speak for where exposure to one antigen results in at least a partial immune response to related antigens. What Edward Jenner achieved — inoculating people with the relatively innocuous cow pox and thus giving them immunity to the far more dangerous smallpox — is an example of strong cross-reactivity. [*] Hmm, could be be seeing inoculation with common-cold coronaviruses?

Staying on the immunity topic, reader Cathe Smith drew my attention to this recent paper in NATURE Communications: https://doi.org/10.1038/s41467-020-16505-0 Let me just give a teaser:

To address the urgent need for a medical countermeasure to prevent the further dissemination of SARS-CoV-2 we have employed a synthetic DNA-based vaccine approach. Synthetic DNA vaccines are amenable to accelerated developmental timelines due to the ability to quickly design multiple candidates for preclinical testing, scalable manufacturing of large quantities of the drug product, and the possibility to leverage established regulatory pathways to the clinic. Synthetic DNA is temperature-stable and cold-chain free, important features for delivery to resource-limited settings7. Specifically for the development of a COVID-19 vaccine candidate, we leveraged prior experiences in developing vaccine approaches to SARS-CoV8, and our own experience in developing a MERS-CoV vaccine (INO-4700)9,10, as well as taking advantage of our vaccine design and manufacturing pathway previously utilized for the Zika vaccine candidate, GLS-570011, which was advanced to the clinic in under 7 months. INO-4700 and GLS-5700 vaccines are currently in clinical testing.

 

 

 

[*] Cross-reactivity is not limited to pathogens. People who have an allergic reaction to a given antibiotic (e.g. a penicillin), and who are switched to a different antibiotic (e.g., a cephalosporin) may sometimes develop a cross-reaction to the latter (which is from a different “branch” of the same chemical family, beta-lactams).

ADDENDUM: New CDC report on transmission: easily from person to person, less easily via fomites (intermediate objects), unlikely via pets. John Campbell clarifies.

 

And via Dr. Seheult, an analysis piece in THE LANCET Diabetes and Endocrinology about vitamin D and COVID19. 

https://doi.org/10.1016/S2213-8587(20)30183-2

Moneygrafs:

A growing body of circumstantial evidence now also specifically links outcomes of COVID-19 and vitamin D status. SARS-CoV-2, the virus responsible for COVID-19, emerged and started its spread in the Northern hemisphere at the end of 2019 (winter), when levels of 25-hydroxyvitamin D are at their nadir. Also, nations in the northern hemisphere have borne much of the burden of cases and mortality. In a cross-sectional analysis across Europe, COVID-19 mortality was significantly associated with vitamin D status in different populations. The low mortality rates in Nordic countries are exceptions to the trend towards poorer outcomes in more northerly latitudes, but populations in these countries are relatively vitamin D sufficient owing to widespread fortification of foods. Italy and Spain are also exceptions, but prevalence of vitamin D deficiency in these populations is surprisingly common. Additionally, black and minority ethnic people—who are more likely to have vitamin D deficiency because they have darker skin—seem to be worse affected than white people by COVID-19. For example, data from the UK Office for National Statistics shows that black people in England and Wales are more than four times more likely to die from COVID-19 than are white people.

[…]
Rose Anne Kenny (Trinity College Dublin, University of Dublin, Ireland) led the cross-sectional study into mortality and vitamin D status and is the lead investigator of the Irish Longitudinal Study on Ageing (TILDA). She is adamant that the recommendations from all public health bodies should be for the population to take vitamin D supplements during this pandemic. “The circumstantial evidence is very strong”, she proclaims regarding the potential effect on COVID-19 outcomes. Adding, “we don’t have randomised controlled trial evidence, but how long do you want to wait in the context of such a crisis? We know vitamin D is important for musculoskeletal function, so people should be taking it anyway”. Kenny recommends that, at the very least, vitamin D supplements are given to care home residents unless there is an extremely good reason not to do so.
Adrian Martineau (Institute of Population Health Sciences, Barts and The London, Queen Mary University of London, UK), lead author of the 2017 meta-analysis has joined with colleagues from universities around the UK to launch COVIDENCE UK, a study to investigate how diet and lifestyle factors might influence transmission of SARS-CoV-2, severity of COVID-19 symptoms, speed of recovery, and any long-term effects. They aim to recruit at least 12 000 people and to obtain interim results by the summer. Despite his enthusiasm for the study, Martineau is pragmatic: “At best vitamin D deficiency will only be one of many factors involved in determining outcome of COVID-19, but it’s a problem that could be corrected safely and cheaply; there is no downside to speak of, and good reason to think there might be a benefit”.
 

And now Dr. Anthony Fauci has warned that staying closed for too long could cause irreparable damage.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

COVID19 update, 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 21, 2020: Colchicine; more on COVID19-related pneumonia and “stealth hypoxia”; community testing in Los Angeles; Belgium as seen from Germany

(1) Via Mrs. Arbel, here is info on a clinical trial of the ancient-as-dirt drug colchicine. This has been in use since Antiquity for the treatment of gout (full disclosure: I have been taking it for a while, when a low-carb, high-protein diet intended to lose weight gave me a painful bout of this “rich man’s disease”): this clinical trial investigates whether its early administration to COVID19 patients may prevent “cytokine storm”. (More here at Physician’s Weekly) https://www.physiciansweekly.com/anti-inflammatory-drug-colchicine-on-deck-for-covid-19/

I am wondering more than ever whether the vast majority of dead from COVID19 aren’t killed by the patients’ own immune systems going amok. (This was what caused most deaths during the 1918 “Spanish” Flu: the main difference with the present epidemic — other than the causative agent which was an influenza virus then, a coronavirus now — is that in COVID19 the severe disease picture seems to be the exception rather than the rule, statistically speaking.

How rare? Consider Israel, which tests reasonably broadly and is conservative about diagnoses, albeit admittedly has a “younger” population pyramid than most Western countries. The screenshot below is from the daily report by its Ministry of Health: https://govextra.gov.il/ministry-of-health/corona/corona-virus/  

As of the time of writing, we have 13,883 verified cases (read: people testing positive for the virus): 9,072 of them in mild condition, 135 in moderate condition, just 142 in severe condition of which 113 on respirators, 181 deceased (of course, 181 too many), and 4,353 verified recoveries — defined here as previously diagnosed, now without symptoms and testing negative for the virus. (The “170” at the top of the graph are new cases added.) Moderate+severe+dead together is 4% (four percent) of the total infected. (Probably closer to 8% or 10% of symptomatic/overt cases — since anecdotally, it seems that about half of Israel’s verified “cases” [read: verified infections] are completely asymptomatic.)

(2) “masgramondou” Emailed me this one from the NYT (original link: https://www.nytimes.com/2020/04/20/opinion/coronavirus-testing-pneumonia.html?action=click&module=Opinion&pgtype=Homepage archived here http://archive.is/QSBfc) in which an emergency physician named Richard Levitan MD at Bellevue Hospital in NYC talks about “stealth hypoxia” in COVID19 patients. Unlike the usual fodder at the NYT, this is a factual report with no obvious political axe to grind. Some moneygrafs:

And here is what really surprised us: These patients did not report any sensation of breathing problems, even though their chest X-rays showed diffuse pneumonia and their oxygen was below normal. How could this be?

We are just beginning to recognize that Covid pneumonia initially causes a form of oxygen deprivation we call “silent hypoxia” — “silent” because of its insidious, hard-to-detect nature.

Pneumonia is an infection of the lungs in which the air sacs fill with fluid or pus. Normally, patients develop chest discomfort, pain with breathing and other breathing problems. But when Covid pneumonia first strikes, patients don’t feel short of breath, even as their oxygen levels fall. And by the time they do, they have alarmingly low oxygen levels and moderate-to-severe pneumonia (as seen on chest X-rays). Normal oxygen saturation for most persons at sea level is 94 percent to 100 percent; Covid pneumonia patients I saw had oxygen saturations as low as 50 percent.

[…]

A vast majority of Covid pneumonia patients I met had remarkably low oxygen saturations at triage — seemingly incompatible with life — but they were using their cellphones as we put them on monitors. Although breathing fast, they had relatively minimal apparent distress, despite dangerously low oxygen levels and terrible pneumonia on chest X-rays.

We are only just beginning to understand why this is so. The coronavirus attacks lung cells that make surfactant. This substance helps keep the air sacs in the lungs stay open between breaths and is critical to normal lung function. As the inflammation from Covid pneumonia starts, it causes the air sacs to collapse, and oxygen levels fall. Yet the lungs initially remain “compliant,” not yet stiff or heavy with fluid. This means patients can still expel carbon dioxide — and without a buildup of carbon dioxide, patients do not feel short of breath.

Patients compensate for the low oxygen in their blood by breathing faster and deeper — and this happens without their realizing it. This silent hypoxia, and the patient’s physiological response to it, causes even more inflammation and more air sacs to collapse, and the pneumonia worsens until their oxygen levels plummet. In effect, the patient is injuring their own lungs by breathing harder and harder. Twenty percent of Covid pneumonia patients then go on to a second and deadlier phase of lung injury. Fluid builds up and the lungs become stiff, carbon dioxide rises, and patients develop acute respiratory failure.

By the time patients have noticeable trouble breathing and present to the hospital with dangerously low oxygen levels, many will ultimately require a ventilator.

Silent hypoxia progressing rapidly to respiratory failure explains cases of Covid-19 patients dying suddenly after not feeling short of breath. (It appears that most Covid-19 patients experience relatively mild symptoms and get over the illness in a week or two without treatment.)

And then the best part!

There is a way we could identify more patients who have Covid pneumonia sooner and treat them more effectively — and it would not require waiting for a coronavirus test at a hospital or doctor’s office. It requires detecting silent hypoxia early through a common medical device that can be purchased without a prescription at most pharmacies: a pulse oximeter.

Pulse oximetry is no more complicated than using a thermometer. These small devices turn on with one button and are placed on a fingertip. In a few seconds, two numbers are displayed: oxygen saturation and pulse rate. Pulse oximeters are extremely reliable in detecting oxygenation problems and elevated heart rates.

Pulse oximeters helped save the lives of two emergency physicians I know, alerting them early on to the need for treatment. When they noticed their oxygen levels declining, both went to the hospital and recovered (though one waited longer and required more treatment). Detection of hypoxia, early treatment and close monitoring apparently also worked for Boris Johnson, the British prime minister.

Widespread pulse oximetry screening for Covid pneumonia — whether people check themselves on home devices or go to clinics or doctors’ offices — could provide an early warning system for the kinds of breathing problems associated with Covid pneumonia.

Read the whole thing.

(3) (via Instapundit) KTLA reports on a new community antibody study in Los Angeles County https://ktla.com/news/local-news/l-a-county-officials-to-provide-latest-update-on-coronavirus-crisis/?fbclid=IwAR3ItNdY_00D6FkDjQRn-x5rK71A2XqLg-xgvPQFSN0YfI9batMXXNA6-s0  which corroborates various earlier reports that the USA, at least, may have a very significant Dunkelziffer/“stealth infection rate”.

While Los Angeles County has reported a total of 13,816 coronavirus cases, early results from an antibody study conducted with the University of Southern California shows that hundreds of thousands more could have had COVID-19 in the past, officials announced Monday.

So far, 863 L.A. County residents have been tested between April 10 and 14 as part of the study.

The study estimates a prevalence of COVID-19 antibodies in the county to be 4.1%, with a range that could be as low as 2.8% and as high as 5.6%, when you factor in the reliability of the tests.

An estimated 221,000 adults to 442,000 adults at the high end may have been infected at some point before April 9 with COVID-19, suggesting that the number of total people in the county with a past or current infection is 28 to 55 times higher than the number of reported positive cases, Dr. Barbara Ferrer, L.A. County’s public health director said Monday.

[…]

Although the sample size was relatively small, Ferrer shared some early estimates about who was most likely to be infected:

Men were more likely than women to be infected. The estimated prevalence is 6% among men and 2% among women

7% of African Americans, 6% of whites, 4.2% of Asians and 2.5% of people who were Latinx who were tested were found to be positive for COVID-19

2.4% of people who were between the ages of 18-34 were positive

5.6% were between 35 and 54

4.3% who were 55 and older tested positive

(4) And in what is rather distressing reading, Die Welt (in German) wonders why neighboring Belgium (!) has the highest pro capita COVID19 mortality in the world — actually, the absolute numbers are larger than Germany’s, which has seven times the population of Belgium! Summarizing a few of their points:

(a) Belgium counts deaths “with” COVID19 as COVID19 deaths, in the name of “transparency”, even if the cause of death is different. Germany uses a  more restrictive definition.

(b) 50-70% of all deaths in Belgium are in homes for the elderly [about 20% of care home residents over 85 test positive in facilities where everybody was tested]. Die Welt cites a report in Belgium’s largest French-language daily, LE SOIR  Wie die Tageszeitung „Le Soir“ berichtet]  Staff went around without even face masks for weeks because of (c)

(c) there is an acute shortage of PPE, particularly masks. The emergency stockpile (from SARS days) had been destroyed pre-epidemic as it had passed the expiration date — and had not been replenished even though that could then easily have been done. (Now Belgium was forced to startup domestic production. [Becoming dependent on China is a recipe for disaster across the world.])

(d) Nevertheless, it’s not all doom and gloom. Spread in the general population has been contained, the number of cases grows more slowly, and the number of deaths has peaked and is now holding at about 300/day. But this is cold comfort, or as you say in both Dutch and German, “meager comfort”…

(e) Finally, as things are again picking up at my day job, I am grateful to the people who have started sending me article tips! 

COVID19 update, April 18, 2020: community testing in Silicon Valley reveals huge “stealth infection numbers” — or does it?

A group of researchers around Eran Bendavid of Stanford (John Ioannides was among the many co-authors) yesterday released the results of their community testing effort in Santa Clara County, CA, as a preprint on MedRXiv: http://doi.org/10.1101/2020.04.14.20062463

Santa Clara County (where I was on assignment for a couple of years) is basically Silicon Valley: Palo Alto (of Stanford University fame), Mountain View (where Google’s campus is located), Sunnyvale, Cupertino (basically Apple City at this point), San Jose, and the like. As the authors explain:

At the time of this study, Santa Clara County had the largest number of confirmed cases of any county in Northern California (1,094). The county also had several of the earliest known cases of COVID-19 in the state – including one of the first presumed cases of community-acquired disease – making it an especially appropriate location to test a population-level sample for the presence of active and past infections.

So they recruited 3,439 volunteers through location-targeted ads on Facebook, and administered antibody tests to them. After discarding unusable results (unable to draw blood, volunteer appeared from outside county,…) this left them with 3,330 data points. The novel kit (Premier Biotech, Minneapolis, MN) they were using is not yet FDA-approved, so they ran calibration tests themselves at a Stanford lab, using positive and negative control samples [1].
Then they reweighted the results by sex (the sample skewed female), ethnicity, and ZIP code distribution to more closely match the overall Santa Clara County population. They also corrected for the test kit’s performance.

The results look like a bombshell, suggesting a Dunkelziffer (dark [case] number, stealth [case] number) as high as 50:1 or even 85:1.

The unadjusted prevalence of antibodies to SARS-CoV-2 in Santa Clara County was 1.5% (exact binomial 95CI 1.11-1.97%), and the population-weighted prevalence was 2.81% (95CI 2.24-3.37%). Under the three scenarios for test performance characteristics, the population prevalence of COVID-19 in Santa Clara ranged from 2.49% (95CI 1.80-3.17%) to 4.16% (2.58-5.70%). These prevalence estimates represent a range between 48,000 and 81,000 people infected in Santa Clara County by early April, 50- 85-fold more than the number of confirmed cases.

However (hat tip: Alex Pournelle, son of the late lamented Jerry Pournelle) biotech entrepreneur Balaji Srinivasan (himself a Stanford Ph.D.) posted an elaborate peer review on Medium in which he criticizes the statistical and sampling methodology of the authors. Let me summarize his two main critiques: (1) He points out that even the small number of false positives found in the manufacturer’s test calibration (none were found in Stanford’s own recalibration, but that is quite possible given the small sample) might mean a significant chunk of the detected rate could be false positives.
(2) In addition, as COVID19 tests were very hard to come by in Santa Clara County (or anywhere else) at the time, respondents to the ad would be self-selected for people suspecting they had COVID19 at some point, being unable to get tested for love or money, and jumping at the opportunity to get tested for free (my paraphrase).

While (1) would make me look toward the low end of the 95% confidence interval of the authors, the effect of (2) is hard to quantify. The authors would presumably retort that the two whole-community testing efforts known — Robbio, Italy (10%) and Gangelt, Germany (14%) — obtained even higher infection rates.

Erik Wingren drew my attention to an even more peculiar finding: in Boston, the denizens of a homeless shelter were tested [2]. “Of the 397 people tested, 146 people tested positive. Not a single one had any symptoms. […] The 146 people who tested positive were immediately moved to two different temporary isolation facilities in Boston. According to O’Connell, only one of those patients needed hospital care, and many continue to show no symptoms.” On the one hand, you’d expect this population to be extra vulnerable — on the other hand, some might argue that anybody who can survive on the streets for an extended period of time, exposed to every possible and impossible community pathogen, likely would have built up a pretty solid immune response. On the gripping hand [3], this is a completely novel pathogen. Any coronaviruses they would have been exposed to thus far would be a subset of common colds. (Most common colds are actually caused by rhinoviruses, which are a different family.)

The results of Eran Bendavid et al. appear to imply that the actual infection fatality rate (IFR) of COVID19 is closer to the 0.1% of a nasty seasonal flu — which of course would have drastic public policy consequences. Taking into account the criticisms of the open peer reviewer would revise the IFR upwards — but still nowhere near the 5-10% CFRs (case fatality rates) thrown around for some countries with problematic testing availability.
I would say that this 0.1% represents a lower bound for the IFR, and the about 1.15% IFR found in Israel (which counts asymptomatic positive cases as patients) with a “young” population pyramid, and the about 3.1% CFR (case fatality rate) with a much “older” population pyramid found in Germany, can be taken as upper bounds. (I note that the preprint of Bendavid et al. makes no mention of age distribution adjustment explicitly says “We did not account for age imbalance in our sample” — which is significant considering morbidity and especially mortality go up strongly with age.)
Iceland continues to test more people, at this point reaching 11% of its entire population (by far the largest of any country). They found 1,754 confirmed infections out of 39,536 tested, or 4.4% — but with a truly self-selecting sample (anybody who wants to do so can get tested for free in Iceland — but this sample would obviously be skewed toward people who suspect they may have been exposed). They have seen only 9 deaths — corresponding to an infection fatality rate of 0.5% that I suspect is fairly close to the true IFR for a typical European age pyramid.

FOOTNOTES:
[1] “Among 37 samples of known PCR-positive COVID-19 patients with positive IgG or IgM detected on a locally-developed ELISA test, 25 were kit-positive. A sample of 30 pre-COVID samples from hip surgery patients were also tested, and all 30 were negative. The manufacturer’s test characteristics relied on samples from clinically confirmed COVID-19 patients as positive gold standard and pre-COVID sera for negative gold standard. Among 75 samples of clinically confirmed COVID-19 patients with positive IgG [antibodies], 75 were kit-positive, and among 85 samples with positive IgM [antibodies], 78 were kit- positive. Among 371 pre-COVID samples, 369 were negative.”

[2] A discussion of homelessness in the USA, and its relation to the deinstitutionalization movement, would be fodder for another (perhaps future) blog post.

[3] I couldn’t resist the Niven/Pournelle reference

UPDATE: John Campbell in his video today mentions both the Stanford study and the Boston homeless shelter, and points out a Dutch dataset I wasn’t aware of. They checked blood of 10,000 regular blood donors for antibodies. 3% of all samples had COVID19 antibodies. Since John cannot see how blood donors would somehow be more susceptible for infection than the general population, he assumes the 3% figure is representative of the infection rate in the Dutch population. With a population of 17.3m, that implies 519,000 Dutch have been infected (most of them apparently asymptomatic or with mild symptoms they misattributed to common colds or flus) — about 3% of the Dutch population, surprisingly similar to the Stanford study, and about 17x more than the official 30,619 cases diagnosed. This also implies the actual IFR in the Netherland is not 3,459/30,619=11.2%, but 1/17th that=0.66%. Hmm… not far from the 0.5% or so from the Iceland data…

COVID19 update, April 11, 2020: (1) how much of the COVID19 iceberg is below the waterline? (2) Miscellaneous updates

Lots ado now about “how much of the iceberg is below water”. In Germany and Austria they call this the “Dunkelziffer” (literally: “dark number”), i.e. how many people got infected and never diagnosed because either they never got sick, or had a mild form which they shrugged off as a garden-variety winter cold. You can already see the policy implications:  not only would this drastically reduce the assumed IFR (infection fatality rate), but it might imply that a nontrivial segment of the community might already have acquired antibodies for the virus. Not enough for true herd immunity, mind you, but even percentages as low as 15% would put a crimp on the reproductive number of the infection.

Several initiatives have been going on around the world to resolve this question. I already discussed Iceland in a previous blog post. Everybody there can get tested, and about 8.5% of the population (by far the largest percentage of any nation) has. This self-selected sample turned out to have about 50% of positives asymptomatic. (This squares with anecdotal evidence here in Israel.)

A community testing initiative is currently proceeding in Silicon Valley, led by Prof. Eran Bendavid of Stanford. 

https://www.sacbee.com/news/coronavirus/article241855856.html This was in part prompted by the intriguing observation that California’s death toll of 541 (as of April 9) is an order of magnitude lower than that of NYC alone! Plausible alternative explanations can be advanced — the highly congested character of NYC and widespread reliance on crowded public transit — David S. Bernstein pointed out to me that the hardest-hit counties per capital of NY state are not Manhattan (as one might naively expect), but “commuter counties” like Nassau and Long Island. 

Meanwhile, Germany and Austria have some first results about  the “Dunkelziffer”. AUSTRIA has released intermediate results from a random sample test of (thus far) 1,544 people: the study is now expanding its sample.  The official infection rate is 0.1%; the study finds 3 times that, but upon closer reading, the 95% confidence interval stretches from 0.12 to 0.76%. This absurdly large uncertainty band should narrow as the sample size increases: all else being equal, the width of the interval will be inversely proportional to the square root of the sample size. So to narrow the uncertainty by a factor of ten, they should test about a hundred times as many people.

In Germany, a virologist named Hendrik Streeck, head of the virology institute at Bonn University, took a different tack: he played “test everybody, sample everything” in the nearby small town of Gangelt (pop. 12,446 ) in the Heinsberg district (on the Dutch border). Heinsberg saw a massive outbreak about two weeks ahead of the rest of the German Federal Republic — it is broadly assumed that ‘super-spreader’ events took place at Carnival celebrations in Gangelt. [The somewhat sleepy Belgian town of Alken, best known for its Cristal brewery, became Ground Zero in that country in the same way.]

Testing is both for the viral RNA and for antibodies. A few takeaways from the study (German writeup in the Handelsblatt; another German writeup in Die Zeit; English writeup in Reason magazine )

• 80% of the population of Gangelt was tested
• 15% of the population has been infected at one point. [In contrast, Germany officially has 122,171 cases, out of a population of 83,783,942 — fewer than 0.15%. However, the infection rate in Germany is very heterogenous.
• 14% of the population has antibodies for the disease
• IFR (infection fatality rate) for the community is then calculated as 0.37%, compared to 2.24% from the national statistics. I infer that testing nationwide has been under-sampling by a factor of 5.5, and that thus there are about 4-5 “cases below the waterline” for every known case — people who never got sick at all, or had mild symptoms they misattributed to a common cold or a seasonal flu
• Streeck believes that even these 15% may be contributing to herd immunity
• While he has found traces of viral RNA on doorknobs, TV remotes, etc. in the houses of infected people (in one case even in the toilet water), there was no indication of viable virus particles that could cause an infection. He sees close and prolonged contact with carriers as the primary way of virus spreading, via droplets getting breathed or coughed upon others

This study has come under fire from German colleagues for methodological reasons, but the state government of North Rhine-Westfalia, which bankrolled the study, stands by Streeck

Elsewhere:

(1) a must-read article by Matt Ridley, a veteran popular science writer with a Ph.D. in biology, who also happens to be a member of the British House of Lords (as the 5th Viscount Ridley): “The bats behind the pandemic”. (The Wall Street Journal version is paywalled, but a free version is available on his blog.) Some of the content is also discussed in a highly entertaining 1h video interview with Ridley, where he also tells it like it is about the Pekinese Lapdog Society, er, the WHO.

(2) The Daily Telegraph looks at the search for a vaccine: https://www.telegraph.co.uk/global-health/climate-and-people/race-covid-19-vaccine-much-politics-science/ Their main source appears to be this article in Nature Reviews Drug Discovery: https://www.nature.com/articles/d41573-020-00073-5
according to which there are no fewer than 120 candidates are in development, 78 of them projects known to be active, six of those in Phase I clinical trials.

(3) A research group at the University of Hohenheim, Germany has put online a simple simulator for different containment measures. As always, a model is not reality: your mileage may vary. But this ‘toy model’ can be informative to experiment with nevertheless.

(4) Now not just in the US, but also in the UK, some ICU doctors are reconsidering invasive ventilation — does it actually do more harm than good? — and shifting focus to noninvasive techniques (oxygen cannulas, O2 concentrators, O2 masks).  Current treatment protocols are based on experience with ARDS (acute respiratory distress syndrome) by other causes — and there are indications COVID-19 is a different ball game.

I talked to a veteran medical professional in my own family (many thanks, “Yehuda”) and got a nuanced answer: paraphrasing, “it may be that the people put on invasive ventilation were basket cases to begin with and therefore would have had a high mortality in any case, but intubation is a tricky business requiring sedation and curarization to even enable the intubation — and with any tricky procedure, the success rate often depends on the skill of the person doing it.” This implies then that the limiting factor isn’t so much the availability of “ventilators” as the availability of personnel skilled in intubation. Noninvasive ventilation is of course way easier to do.

UPDATE: the first clinical trial results, in a population of severe and critical cases, of remdesivir (originally developed by Gilead Sciences for ebola) were published in the New England Journal of Medicine https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal mem- brane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

A list of additional remdesivir clinical trials in progress can be viewed here.