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, 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.