A call for the importance of asymptomatic cases in the spread of Covid-19 involving studies from China, Italy and Japan. Bear in mind, read this opinion at your own risk — it is not a peer reviewed scientific evaluation & publication, but based on 2 months of observation collecting the cases available for the existence and impact of asymptomatic cases — I will call here DARK NUMBERS.

Because we are also in a veritable crisis of crisis communication, it is difficult for laymen and experts to find common ground in what to believe. We are not in a war of opinions or belief systems (this is not a political debate), but we seem to have difficulties to trust scientifically valid observations if something is happening or not–a new reality. In all that storytelling, the fiction which ruled our life till now, there is (now) a benchmark, a result of our ever dubious pondering: do our predictions and actions match with the unfolding events out there, or not. Is someone getting sick nor not? Are Emergency rooms / ICUs overstretched or not, does the virus SARS-Cov-2 infect human cells and multiplies there, or not? Do we carry it around in substantial numbers also infecting others unknowingly, or NOT? My suspicion was already in the first three weeks of March that dark numbers may rule the scenario somehow — or not — and if there is hard evidence and justified reason to think so. We do not have the full picture, which is still true after Easter at the 14/04/2020…or after 29/05/2020 (2nd update), 15/06/2020 (3rd update) or on 16/07/2020 (last update).

Covid-19 is still no fake news and no “simple influenza”. We are aware of this worldwide, a bitter reality which is overloading health systems, killing people, harming the sick, disrupting economies and scaring populations of many countries RIGHT NOW (the virus is now present in 180 countries) and in the times to come — if we are not finding treatments for the severe cases or a vaccine. We went from containment to mitigation all too quickly, even though it was often not an outspoken shift, more like a forced one. Containment was not attempted early on and therefore not successful in most of the Western countries, which responsible officials have to answer for. New Zealand and Taiwan may qualify as successful containment, because they managed infection rate, death toll and economic fall out without a lockdown. While there is still much of discussion ongoing how bad it will be, and some regions are already easing the measurements it is not a question, IF it is happening, but HOW BAD will it become?

In Italy, where I live right now, we had 46,638 positively tested people, 5,476 deaths and 7,024 cured on 22/03/2020. Roughly 3 weeks later, on Easter Sunday 13/04/2020 there were officially 159,516 positively tested cases, 20,465 deaths and 35,435 cured. Another 1 1/2 months later, there are accumulatively 232,248 positively tested, 33,229 deaths and 152,844 cured on 29/05/2020 — which became 237,290 positively tested, 34,371 deaths and 177,010 cured till 15/06/2020.(http://www.salute.gov.it/portale/nuovocoronavirus/dettaglioContenutiNuovoCoronavirus.jsp). While the USA are “soaring” sadly at ranking №1 meanwhile with 1,725,656 positively tested cases and 101,706 deaths, rising to 2,100,749 positively tested cases and 115,827 deaths till 15/06/2020.(https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6)

WHAT could you LEARN in this article? First, to respect what we DO NOT know about the dynamics of a multi-factorial outbreak situation. The dark numbers I propose as a concept of the all the numbers unaccounted of and tests we did not do so far — or could not do because of Wild West methods of buying or rerouting materials or basic reagents. Second, if we DO NOT know how many people are REALLY infected at a given point in time and they are not to be spotted by symptoms in large numbers, WE ALL NEED TO WEAR MASKS to protect EACH OTHER when we go outside (shopping, working, etc.). Masks as physical barriers protect others from spreading droplets while speaking, coughing or sneezing. That was not made clear from the start and the confusion around masks was also coming from highest levels, the WHO and governments who often simply denied the effectiveness of masks, because they did not HAVE ANY to distribute and left also health care workers unprotected. For the case of France read (in German): https://www.faz.net/aktuell/politik/ausland/nizza-fuehrt-als-erste-franzoeische-grossstadt-maskenpflicht-ein-16716014.html or the backtracing of the WHO: https://edition.cnn.com/2020/03/30/world/coronavirus-who-masks-recommendation-trnd/index.html and then later https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public/when-and-how-to-use-masks

Asymptomatic, pre-symptomatic & aclinical

The “dark numbers” described in this article intend to sum up the unknown quantities of those categories:

People who never develop symptoms (asymptomatic) +

People who test positive when they don’t yet have symptoms — but go on to develop them (pre-symptomatic) +

People with very mild or atypical symptoms who do not realise they have coronavirus (aclinical).

(compare Dr Van Kerkhove, the WHO’s head of emerging diseases in https://www.bbc.com/news/health-52977940, I added the definition “aclinical”)

Evidence suggests people with symptoms are most infectious, but the disease can be passed on before it develops palpable symptoms.

In May 28th 2020 a fact checked article citing some of the studies analysed here as well ranges the amount of asymptomatic cases in between 25–80% of Covid-19 cases. (see Health News, ”As Many as 80 Percent of People with COVID-19 Aren’t Aware They Have the Virus” https://www.healthline.com/health-news/50-percent-of-people-with-covid19-not-aware-have-virus)

In The Washington Post Daniel Oran & Eric Topol (of the digital medicine group at the Scripps Research Translational Institute. Eric J. Topol, a professor of molecular medicine at Scripps Research, is founder and director of SRTI) were giving another overview of the importance of asymptomatic cases on June 11, 2020 in stating:

In assessing the overall rate of asymptomatic infection, we found some dramatic outliers. For example, among 3,277 prison inmates in four states who tested positive for the coronavirus, an astounding 96 percent had no symptoms at the time of testing. At the other end of the spectrum, a mere 6 percent of 48 infected nursing home residents remained asymptomatic. It appears that a variety of factors, perhaps including age and previous exposure to other, more benign coronaviruses, may account for these extremes.

Although this proportion of people test positive with no symptoms, it is still not known on 15/06/2020 how many of these people go on to infect others, or how much those types of “atypical infections” may become even “superspreaders” (see Chris Kenyon, Letter to the Editor, 01/06/2020 “The prominence of asymptomatic superspreaders in transmission mean universal face masking should be part of COVID-19 de-escalation strategies”, International Journal of Infectious Diseases https://www.ijidonline.com/article/S1201-9712(20)30409-4/pdf). Thus, it may still be crucial to estimate or deduct the percentage of dark numbers from the official numbers and the knowledge we have so far.

The world misses COVID-19’s silent spread early on

If one dares to revisit the first reported cases in Germany in the cluster coming from the Webasto seminar in Bavaria before there was the big alarm in Italy, one would unfold the long story of putting asymptomatic spread under the rug since January. On January 27th Dr. Camilla Rothe had her first Covid-19 result of a patient, a man “who could have been infected by only one person: a colleague visiting from China. And that colleague should not have been contagious.”

On the night of Germany’s first positive test, the virus had seemed far away. Fewer than 100 fatalities had been reported worldwide. Italy, which would become Europe’s ground zero, would not record its first cases for another three days.

A few reports out of China had already suggested the possibility of symptomless spreading. But nobody had proved it could happen.

That night, Dr. Rothe tapped out an email to a few dozen doctors and public health officials.

“Infections can actually be transmitted during the incubation period,” she wrote.

The NYT writes further:“Interviews with doctors and public health officials in more than a dozen countries show that for two crucial months — and in the face of mounting genetic evidence — Western health officials and political leaders played down or denied the risk of symptomless spreading. Leading health agencies including the World Health Organization and the European Center for Disease Prevention and Control provided contradictory and sometimes misleading advice. A crucial public health discussion devolved into a semantic debate over what to call infected people without clear symptoms.”

Read the story of German Dr. Camilla Rothe’s team being among the first to warn about asymptomatic transmission (which the Webasto cluster of 9 positive simply was) for yourself: “HOW THE WORLD MISSED COVID-19’s SILENT SPREAD” by Matt Apuzzo, Selam Gebrekidan and David D. Kirkpatrick from 27/06/2020 https://www.nytimes.com/2020/06/27/world/europe/coronavirus-spread-asymptomatic.html

The authors point rightfully out, that the two-month delay was a product of faulty scientific assumptions, academic rivalries and, perhaps most important, a reluctance to accept that containing the virus would take drastic measures. The resistance to emerging evidence was one part of the world’s sluggish response to the virus.

It is too soon to know whether the worst has passed, or if a second or third global wave of infections is about to crash down. But it is clear that an array of countries, from secretive regimes to overconfident democracies, have fumbled their response, misjudged the virus and ignored their own emergency plans. Somebody will have to answer for this, as the result is deadly and ignorance paved with the death toll of innocent people kept in the dark.

These facts shame our health officials and governments who underestimating the importance of a scientific reality— that asymptomatic spread is happening and that the story of how to battle Covid-19 needs to change accordingly.

Official numbers vs. true numbers vs. dark numbers

How to interpret the numbers we are given? Well, we let experts tell us what they might mean given their respective field of study. Too many augurs are mulling over one or the other aspect and extrapolate quickly from a changing dynamic. Staying patient and observing big trends might be the wisest strategy for the citizen. We can all learn from each other as professionals all over the planet try to make sense of this pandemic.

This very well made overview diagram from the study of Zunyou & McGoogan about the unfolding scenario of cases in Wuhan published on 24/02/2020 in the JAMA — Journal of American Medical Association may help here (see figure 1 in https://jamanetwork.com/journals/jama/fullarticle/2762130):

Zunyou & McGoogan in JAMA. Published online February 24, 2020. doi:10.1001/jama.2020. 2648 This figure was adapted with permission. CDC indicates Chinese Center for Disease Control and Prevention; HICWM, Hubei Integrated Chinese and Western Medicine; 2019-nCoV, 2019 novel coronavirus; WHO, World Health Organization.

Thomas Puyeo, a startup entrepreneur and MBA from Stanford has tried to make sense of this diagram and wrote a highly influential medium post explaining these numbers/bars depicted there very well: “The grey bars show the true daily coronavirus cases. The Chinese CDC found these by asking patients during the diagnostic when their symptoms started. Crucially, these true cases weren’t known at the time. We can only figure them out looking backwards: The authorities don’t know that somebody just started having symptoms. They know when somebody goes to the doctor and gets diagnosed.

What this means is that the orange bars show you what authorities knew, and the grey ones what was really happening. We are always behind, looking 2–3 weeks into the past in comparison to what is happening now.

On January 21st, the number of new diagnosed cases (orange / official cases) is exploding: there are around 100 new cases. In reality, there were 1,500 new (true) cases that day, growing exponentially. But the authorities didn’t know that. What they knew was that suddenly there were 100 new cases of this new illness.

Two days later, authorities shut down Wuhan. At that point, the number of diagnosed daily new cases was ~400. Note that number: they made a decision to close the city with just 400 new cases in a day. In reality, there were 2,500 new cases that day, but they didn’t know that.The day after, another 15 cities in Hubei shut down.

Up until Jan 23rd, when Wuhan closes, you can look at the grey graph: it’s growing exponentially. True cases were exploding. As soon as Wuhan shuts down, cases slow down. On Jan 24th, when another 15 cities shut down, the number of true cases (again, grey) grinds to a halt. Two days later, the maximum number of true cases was reached, and it has gone down ever since.

Note that the orange (official) cases were still growing exponentially: For 12 more days, it looked like this thing was still exploding. But it wasn’t. It’s just that the cases were getting stronger symptoms and going to the doctor more, and the system to identify them was stronger. This concept of official and true cases is important.” (from https://medium.com/@tomaspueyo/coronavirus-act-today-or-people-will-die-f4d3d9cd99ca some of the text set in bold my emphasis, the parts set inverse are my clarifications)

Still, this might not be the full picture…

Asymptomatic cases are missing in this account and they do not play into the official numbers, because they very rarely got tested and thus, registered. The statistics to show the true numbers from official ones working backwards and estimating the true ones are fine — ONLY it if they would encompass the asymptomatic ones, too. Those, who might NOT get sick themselves, but contribute (in a yet unknown amount) to the epidemiology of Covid-19.

There is an elephant in the room, probably explaining a lot of the spread: dark numbers, or asymptomatic cases who stay aclinical (or subclinical) and do not develop symptoms (or only very mild ones one might not really recognise). How many are these? If we cannot screen for temperature or feeling sore or “sick”, cough, headache or throat ache, how shall we contain the virus? It seems to be proven that (unlike SARS) in Covid-19 cases people are already infective without symptoms (but may develop them at a later stage) AND that there is a significant percentage of “asymptomatic cases” which may NEVER develop symptoms but prove to be SARS-Cov-2 positive AND are spreaders. This calls quarantine and screening into question, but social distancing and wearing a mask is still the best way to fight a spread, BECAUSE we do not know who has it (or will get sick soon). I call them (to distinguish from Thomas Pueyo using “true” case) dark numbers.

The IHS — Institute for Higher Studies in Vienna (Austria) thinks there are about 76% asymptomatic cases to expect and they also hint to the Italian community of Vò and a study of Univ. of Padua conducted there, at the first known cluster of the Covid-19 outbreak in Italy. See (in German) https://www.derstandard.at/story/2000115987433/zu-wenig-tests-zu-viel-spekulation-um-die-dunkelziffer

So, the dark numbers need to be differentiated into true numbers and asymptomatic ones, staying dark, because they do not get properly measured, because people do not get sick enough to notice, but might still spread the virus.

The case of Vò (Italy)

The most stricken country in Europe has its own “Wuhan”, a place called Vò in Veneto next to Padua. There, possible asymptomatic cases could get tested and studied being cordoned off by military forces. In a study of this first location of the outbreak in Italy this part of infected humans are called ‘submerged’ infections. It got conducted by Andrea Crisanti, Direttore della Cattedra dell’Unità Diagnostica di Microbiologia e Virologia dell’Università di Padova. https://www.trialsitenews.com/university-of-padua-vo-study-one-possible-hypothesis-of-how-to-contain-covid-19/ with the following blunt result:“The percentage of infected people, even if asymptomatic, in the population is very high.” A professor (Professor Sergio Romagnani of the University of Florence) interpreting the study, was saying, “The isolation of asymptomatic is essential to be able to control the spread of the virus and the severity of the disease.” In La Republicca Prof. Romagnani (who is a former teacher of Prof. Andrea Crisanti) is quoted to estimate the asymptomatic cases to be 50–75%: “The vast majority of people infected with Covid-19, between 50 and 75%, are completely asymptomatic but represent a formidable source of contagion.” — Italian original: “La grande maggioranza delle persone infettate da Covid-19, tra il 50 e il 75%, è completamente asintomatica ma rappresenta una formidabile fonte di contagio”. https://www.repubblica.it/salute/medicina-e-ricerca/2020/03/16/news/coronavirus_studio_il_50-75_dei_casi_a_vo_sono_asintomatici_e_molto_contagiosi-251474302/

10/03/2020 Andrea Crisanti, the leader of the study in Vò has outlined his learnings and strong suggestions from the data gathered there, the “model of Vò”. Testing was early and the tested symptomatic and asymptomatic cases were isolated, so the rate of infection dropped significantly. One of the big Italian newspapers brought the story, arts of the interview in Corriere della sera translated from Italian by me, explaining the approach, see the Italian original here: https://www.corriere.it/salute/malattie_infettive/20_marzo_10/crisanti-tamponi-massa-zone-focolaio-c-poco-tempo-df2e2036-6239-11ea-9897-5c6f48cf812d.shtml

How old were the infected people? “Half of them were elderly people who did not develop serious forms: an unexpected fact, which we are still studying.”

Can the «Venetian model» be exported to other Italian regions? “The goal is to control the epidemic in the early stages, also to limit the severity of clinical manifestations. I believe that the approach chosen for Vo ‘can be used to close the outbreaks existing in our country — starting from Veneto, Marche, Emilia-Romagna — and then concentrate efforts in Lombardy. But we must hurry, time is not on our side ».

What do you recommend to do in practice? «Wherever there are outbreaks, carry out mass tests on the population and trace the contacts of the positive (more or less close), then isolate all the infected, even if they are asymptomatic. It takes aggressive action, otherwise the virus will continue to circulate. The alternative is the Chinese way, all closed for 3 months without exception. “

Is it an economically sustainable program? “A test (tampon) costs 30 euros, a patient in intensive care from 3 to 5 thousand euros per day.”

How do you assess the situation in Lombardy? “It is very submerged, it is necessary to make it emerge, find and isolate all the positive and the related contacts, direct and indirect. Costs what you cost: do you need 5 million tampons? They take it. Lombardy has the resources to do it, but drastic measures are needed ».

12/03/2020 Andrea Crisanti in another interview VVOX in which he demands «mass swabs to eradicate coronavirus»: https://www.vvox.it/2020/03/12/coronavirus-tamponi-veneto-cosa-succede/ and states: “The Region is about to greatly enhance the ability to swab across the region. First of all, we will check all risk categories, all those most exposed to the public: carabinieri, police, cashiers, operators who are in contact with the public, health personnel. Afterwards we will go to the home of all those who complain of symptoms: we will test them, if they are positive we will put them in isolation and we will put all the contacts in isolation, in addition to testing all those within a radius of 100 meters.”

13/03/2020 Andrea Crisanti did an interview in “Il Gazettino” noting:

The real problem is the asymptomatic positives, if we continue to send them around we will never eliminate the epidemic.

https://www.ilgazzettino.it/nordest/primopiano/coronavirus_italia_news_virologo_asintomatici_problema_vero_epidemia-5108698.html

In an interview with sanitainformazione.it Crisanti says on 12/03/2020: “Now in Vo ‘we know how many asymptomatics are, because in the second sampling this 2.5 per thousand (0,25% or in a community of 3,700 = 9 cases, my addition) is all composed of asymptomatics. We have put them in isolation and now theoretically Vo ‘should be safe — continues Crisanti, who has a past as a researcher at Imperial College London -”Surely asymptomatics play an important role. Identifying positive and asymptomatic contacts is a fundamental thing.”

So far the study in Vò does not seem to have gotten published and the real numbers they observed are left obscure and a bit contradictory, as Crisanti has not stated direct data but mostly general learnings. From all that he said, it could point to a 8% ratio of asymptomatics remaining in Vò after 2 weeks — that means 9 of 111 –but that is my augury, deducted from what he said — and it is a little bit strange that we do not get more detailed access to the data or concrete numbers. We will see if the interpretation of Prof. Romagnani concerning 50–75% asymptomatic will hold up over time. I will update this section when I find a link to the conducted finished study. It seems to be clear that the positive cases in Vò were contained by the quarantine measures but also by testing EVERYBODY, to be sure. That is not technically possible yet in any of the countries with a Covid-19 outbreak, and even in South Korea which is following a mass testing strategy not every citizen gets tested.

On 19/03/2020 Crisanti got cited in the Nationalpost.com (see https://nationalpost.com/news/world/how-an-experiment-helped-one-italian-town-find-submerged-infections-cut-new-covid-19-cases-to-zero):

“We were able to contain the outbreak here because we identified and eliminated the ‘submerged’ infections and isolated them,” he said of the Vò approach. “That is what makes the difference.”

The accounts about asymptomatic cases may prove very relevant for the US, which has denied their importance in the initial stages. That changed recently:

“Asymptomatic and mildly symptomatic transmission are a major factor in transmission for Covid-19,” said Dr. William Schaffner, a professor at Vanderbilt University School of Medicine and longtime adviser to the CDC. “They’re going to be the drivers of spread in the community.” Read more about this curated for an audience in the US in a piece by CNN from 19/03/2020: https://edition.cnn.com/2020/03/14/health/coronavirus-asymptomatic-spread/index.html

A less scientific account of this approach for the US can also be found here calling a possible solution the “Veneto model”: https://promarket.org/why-mass-testing-is-crucial-the-us-should-study-the-veneto-model-to-fight-covid-19/

On 23/03/2020 he was speaking in the local TV news/updates TGR Veneto suggesting a plan to focus-test all the high-risk workforce first, also if they do not show symptoms (yet) and then enlarge the number of tests steadily, to catch as many asymptomatic spreaders as possible and protect those who are not infected yet. The numbers of test tampons and facilities to analyse them are limited, so it needs to be a step-by-step plan, in his view. Watch the announcement here (in Italian) https://www.rainews.it/tgr/veneto/video/2020/03/ven-coronavirus-covid19-virologo-Andrea-Crisanti-sorveglianza-attiva-con-tamponi-mirati-fe8591ad-edc7-498a-afd2-4ddbce0b720c.htm

The problem is that there are many asymptomatic people who are not staying at home and still have, although reduced, an ability to socialize and therefore to transmit the virus. Hence the idea of ​​”mass tampons” throughout Veneto and promises to be the only real weapon at the moment to combat the epidemic.

On 29/05/2020 despite announcements (also by Crisanti) mass testing programs including serological tests and swabs are still not getting rolled out or performed. Italy, like many other countries have gradually opened up social and commercial activity (Phase 2) WITHOUT amping up testing capacities, contact tracing for finding new clusters or widespread serological tests for finding the amount of immunity in the population. We are still flying blind…

Narrow focus

“Given the limited testing to date, some deaths and probably the vast majority of infections due to SARS-CoV-2 are being missed. We don’t know if we are failing to capture infections by a factor of three or 300. Three months after the outbreak emerged, most countries, including the U.S., lack the ability to test a large number of people and no countries have reliable data on the prevalence of the virus in a representative random sample of the general population.” Still, Dr. John P.A. Ioannidis, professor of medicine, of epidemiology and population health, of biomedical data science, and of statistics at Stanford University and co-director of Stanford’s Meta-Research Innovation Center is founding his reasoning of the CFR only on the Diamond Princess case and the few cases in comparison in the US, dismissing the work of the Chinese authorities, South Korea or the high CFR in Northern Italy right now (6,5%!) — entirely. There are 72,000 people case scenarios here and I suggest he reads that and asks European fellow colleagues for their unfolding data (31,000 cases in Italy as of yet 19/03/2020 — ). https://www.statnews.com/2020/03/17/a-fiasco-in-the-making-as-the-coronavirus-pandemic-takes-hold-we-are-making-decisions-without-reliable-data/

As you can read in the CNN article cited above, US Secretary of Health and Human Services Alex Azar told host George Stephanopoulos on 01/03/2020 on ABC’s This Week, that

…asymptomatic spread is “not the major driver” of the spread of the new coronavirus.”You really need to just focus on the individuals that are symptomatic,” he said. “It [the containment strategy] really does depend on symptomatic presentation.”

The website for the US Centers for Disease Control and Prevention echoes that assessment, “Some spread might be possible before people show symptoms; there have been reports of this occurring with this new coronavirus, but this is not thought to be the main way the virus spreads,” according to the website.

In contrast, according to Harvard Medical Schoo true cases, not yet registered (or staying unregistered) may be about 50x the registered official cases. Harvard Medical School / Massachusetts General Hospital released their estimate in a video recording of the MGH Medical Grand Rounds of 12/03/2020). You can watch it here: https://externalmediasite.partners.org/…/53a4003de5ab4b4da5… So, if the actual (true) cases are 50x greater than the reported cases, they likely have 75,000 cases not-yet-registered in the United States already, echoes Jason Scott Warner (USA) @medium (15/03/2020 date of the post about statistics & math of Covid-19 where I found this) https://medium.com/@Jason_Scott_Warner/the-sober-math-everyone-must-understand-about-the-pandemic-2b0145881993).

As for 24/03/2020 there were 46,450 positive cases in the US with 593 deaths (see John Hopkins “real-time” data @ https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6). 9 days earlier, on 15/03/2020 there were only 1,678 positively tested according to WHO situation reports (see https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/). Authorities also did not follow up past deaths or cases with similar symptoms — as President Trump still refuses to wear a mask in public, is said to take a untested Malaria drug as a prevention and recommends to drink and inject disinfectants. A mad world, indeed!

In the US the numbers were rising to 582,594 positively tested, 23,649 deaths and total confirmed 1,929,922 cases worldwide and a total of 132,676 deaths until 14/04/2020.(https://www.worldometers.info/coronavirus/worldwide-graphs/#total-deaths)

On 29/05/2020 the numbers WORLDWIDE rose to 5,851,494 positively tested and 361,210 deaths, rising to 7,953,453 positively tested and 434,432 deaths till 15/06/2020. As we might not compare historical numbers daily anymore (and many might have gotten tired with that early obsession), this reveals that we count more than 3,2x the deaths within 2 months (14/04/2020–15/06/2020) in the pandemic — which is somewhat shocking.

Some judge the number of reported cases or a focus on those as not that important, in comparison. Some say it is looking at Covid-related deaths, others at the CFR (Case Fatality Rate), others favour the IFR (Infection Fatality Rate). Because nucleic acid testing (PCR) is limited and currently available primarily to people with significant indications of and risk factors for Covid-19 disease, and because a large number of infections with SARS-CoV-2 result in mild or even asymptomatic disease, the IFR is likely to be significantly lower than the CFR. (see e.g. https://www.virology.ws/2020/04/05/infection-fatality-rate-a-critical-missing-piece-for-managing-covid-19/)

Only all the pieces of the puzzle may give a proper view on that complicated disease rolling over the planet, “unseen” and unheard. There might be a substantial number or unreported cases which stay out of the official numbers, and therefore also out of the estimates of the not-yet-registered ones. I think it locally understandable to focus on the good or bad numbers at hand, but in a world where we are all battling the same phenomena it seems scientifically hazardous to not listen at all to colleagues from abroad. If you are only considering what is happening around the corner of your office, in your city or –or not much less narrowly– within the fictional, arbitrary borders of a nation, you miss the big picture. The virus knows no borders and searches the opportunity to travel and multiply not within abstract governmental concepts, bodies of text or plans of health associations, but within the bodies of human beings. Singular ones, who want to physically meet others. We need to listen to each other and build up networks of trust, if we want to battle planetary threats more efficiently together.

The broad picture

Stubbornly following individual paths may just isolate countries and offer gaps to step in for rivals. All the doctrines of “…. FIRST!” might crumble to dust if they are in need of help, having misjudged the situation. Often the responsible ones seem not to have listened to the experts and straightforward voices, but to petty economic considerations and national whispers, suggesting political gain for this and that, delaying action.

Bill Gates, often mistakenly and stupidly vilified for his philantropic endeavours, was writing as early as February 28, 2020 about the threat of asymptomatic cases in the New England Journal of Medicine. Yes, THIS Bill Gates. As a billionaire who donated 50% of his wealth he does fund medical research for years, and despite not being a doctor or virologist he has a voice and a weight, other than some super-rich only vegetating on their yachts: https://www.nejm.org/doi/full/10.1056/NEJMp2003762

In a German study of 126 evacuees from Wuhan there were 2 asymptomatic cases found which got missed by thorough symptom screenings. A group of predominantly German nationals who had stayed in Hubei Province was evacuated to Frankfurt, Germany, on February 1, 2020. They were to be transferred to Germersheim, Germany, and quarantined for 14 days. The study got published as a letter of Hoehl et al. in 18/02/2020 to the New England Journal of Medicine including the names of 19 doctors and one specialist, see https://www.nejm.org/doi/full/10.1056/NEJMc2001899

A Japanese study (Nishiura et al. Feb 17/2020 — March 6/2020) of 565 evacuees from Wuhan resulted in a tally of 30,8% asymptomatic cases. Interestingly they note that this ratio is slightly smaller than that of influenza, which was estimated at 56–80% (Hsieh et al., 2014) using similar definitions for symptomatic individuals. This is taken from the .pdf with updates in March. https://www.ijidonline.com/article/S1201-9712(20)30139-9/pdf

(NOTE: The preprint version of this paper from 17.02.2020 shows a higher count still of 41,6% asymptomatic cases: https://www.medrxiv.org/content/10.1101/2020.02.03.20020248v2)

UPDATE: This peer reviewed paper by Li et al. in the magazine Science from the 16/03/2020 reports that:

We estimate 86% of all infections were undocumented (95% CI: [82%–90%]) prior to 23 January 2020 travel restrictions. Per person, the transmission rate of undocumented infections was 55% of documented infections ([46%–62%]), yet, due to their greater numbers, undocumented infections were the infection source for 79% of documented cases. These findings explain the rapid geographic spread of SARS-CoV2 and indicate containment of this virus will be particularly challenging. https://science.sciencemag.org/content/early/2020/03/24/science.abb3221 / Science 16 Mar 2020: eabb3221 DOI: 10.1126/science.abb3221

One may ask the question why the reports of asymptomatic cases are not included in every report and discusses on high priority, and the focus rests still in many countries obstinately on the symptomatic cases they can see and measure more directly. To expand the narrow picture to a broad one means maybe to declare defeat in not having reacted quickly enough, as their decision to focus on observable symptoms may sound easier, but bite back over time, when they are wrong. You cannot properly track down hundreds or thousands of people without symptoms who were contaminating a lot of others unknowingly over a period of a month, unfortunately. That may only work early on with few official numbers and strict and aggressive investigations of possible contact persons, isolating and testing them over and over again, to be sure. The limited number of planned test capacities and funds for that may have closed the time window already — but one might ask why the richest countries in the world, Germany, the USA, France, the UK have opted fo far against throwing a lot of resources onto testing often and quickly — endangering the spread of an unknown virus originating in China, where reports already warned about the problem of asymptomatic cases. This selective ignorance may have caused us the opportunity for containment and all what is left is either suppression or mitigation.

Numbers from China

Can we believe the official numbers from China as prominent German Virologist Alexander Kekulé suggests (hear in the end of the MDR podcast (in German): https://www.mdr.de/nachrichten/podcast/kekule-corona/corona-kompass-kekule-ausbreitung100.html)? I hope so, but hope alone is not enough. The data from China should have informed us since the outbreak in Dec/Jan but there were a lot of voices being critical with the depth and sincerity of communication as the one-party system in China got challenged by suppressing the facts first and reacting slowly, then very drastically.

Supchina, the platform of China news built by veterans of China-watchers Kaiser Kuo (ex-director for international communications for Chinese search engine Baidu) and Jeremy Goldkorn (founder of infamously shut down danwei.org) offered deeper insights into the situation in China. They also run the renowned Sinica podcast for years inviting prominent China journalists and China-watchers to participate in uncensored discussions about Chinese political and economic affairs and their editors usually express a more nuanced opinions. On 09/03/2020 their take on the Chinese numbers sound as follows: “The new official numbers from China, to be taken with a huge grain of salt, especially after Caixin confirmed that asymptomatic — but still contagious! — COVID-19 patients are not being counted in official numbers in many provinces.” (see https://supchina.com/2020/03/09/official-covid-19-cases-fall-in-china-but-can-we-believe-the-numbers/) and later cite e.g. Graham Webster (editor-in-chief, Stanford New America DigiChina Project) on 19/03/2020 when he tweeted:

When Chinese official sources report numbers amidst an unprecedented propaganda campaign and with existential risk to CCP rule on the table, don’t take them literally. Take them as what authorities want you to think and repeat.

Reports from China do indicate that the authorities were very well aware of the threat concerning asymptomatic cases and have known about the contagion risk:

Caixin reported on 01/03/2020: “In its Jan. 28 virus prevention and control plan, the NHC demanded the prompt detection and reporting of those with light or no symptoms. According to the document obtained by Caixin, the Heilongjiang CDC confirmed its first asymptomatic case on Feb. 1 and left the individual off its public list of confirmed cases as per NHC instructions.

In a statement to Caixin, the Heilongjiang CDC said that it was told by the national CDC to “temporarily” include asymptomatic cases in public tallies with confirmed, symptomatic cases. However, after the Feb. 7 release of the fourth edition of the NHC’s Covid-19 guidelines, which reaffirmed that asymptomatic cases should be reported separately and excluded from the confirmed case tally, Heilongjiang removed 13 asymptomatic infected individuals from its “confirmed cases.”

China’s policy has remained in place despite multiple studies from both Chinese and overseas researchers suggesting that individuals infected with Covid-19 can be contagious even if they do not feel ill. (…) Nevertheless, at a Feb. 14 press conference, NHC deputy director Zeng Yixin said that the country would only publicize “suspected” and “confirmed cases.” “If you don’t have symptoms, it’s not an illness,” he said. “There’s no need to announce it.” “If you don’t have symptoms, it’s not an illness,” he said. “There’s no need to announce it.” (see at Caixin, porous paywall, sign-in seems to be for free https://www.caixinglobal.com/2020-03-01/chinas-decision-to-leave-asymptomatic-patients-off-coronavirus-infection-tally-sparks-debate-101522529.html)

Also from this article of Caixin Global is the reaction of Michael Mina, assistant professor of epidemiology and immunology at the Harvard School of Public Health: “Perhaps the most important component at this point is it shows that it may be even more widespread and difficult to contain than we think,” Mina said. “I think any withholding of known figures pertaining to infections not only does a disservice to China’s ability to monitor and help control the epidemic but also inhibits global scientists from being able to learn from and disseminate useful information both back to China and to the global community.”

UPDATE: On 01/04/2020 Caixin added an article titling “China’s Asymptomatic Coronavirus Case Numbers Don’t Tell the Whole Story” in which they write:”The updates to epidemic reports follow at least two calls by Chinese Premier Li Keqiang to focus on containing asymptomatic carriers, which numerous studies have shown to be contagious, as well as public calls for transparency about the size of this population. The NHC announced Tuesday that it would include the latest information on this group in its reports starting Wednesday in an effort to address public concerns.” https://www.caixinglobal.com/2020-04-01/chinas-asymptomatic-coronavirus-case-numbers-dont-tell-the-whole-story-101537553.html

Why do the efforts or lack of efforts around asymptomatic numbers do not reach our TV reports and official government policies in Europe can only be speculated about. They might face the same scenario than in China, not having reacted early enough so that only a lockdown remains as an effective strategy to contain also the asymptomatic cases. Even though transparent communication is paramount specially in democratic societies, authorities might put the asymptomatic cases under the rug, as their lax measures in the first weeks of a spread to Europe did not count in asymptomatic cases and it turned out to be a grave mistake, and they do not want to admit it to keep people following their often perceived “harsh” new rules. Germany jumped from 5.813 on the 15/03/2020 to 32.061 confirmed cases on 24/03/2020, that means 5,5x in 9 days. On 29/05/2020 the positively tested cases in Germany “jumped” to 182.559, coming with 8.497 deaths, rising to 187.602 positively tested and 8.807 deaths till 15/06/2020. The German resilience and “exemplary coping” with the disease got battered down in reality, ranking №8 worldwide on 29/05/2020, only 2 behind Italy — now, on 15/06/2020 ranking №11.

UPDATE: Screening for asymptomatic cases in Wuhan with 9 million tests

Between May 14 and May 23/2020, close to seven million residents were tested. That number later grew to nine million — or 80 per cent of Wuhan’s population. The state-run Health Times reported 198 of the positive cases found were asymptomatic — from people who are carrying the virus but have no idea. Caixin Global reports 206 positive asymptomatic results (see https://www.caixinglobal.com/2020-05-26/mass-testing-finds-more-than-200-asymptomatic-covid-19-cases-in-wuhan-101559009.html) The risk of asymptomatic cases have drawn the Chinese leadership’s attention. On March 30, Premier Li Keqiang stressed that the nation must prioritize control and prevention of those showing no symptoms.

Zhang Wenhong, a top epidemiologist at Huashan Hospital of Fudan University in Shanghai, said in an article posted on social media that based on his team’s research, 18% to 31% of all infected cases turned out to be asymptomatic.

Asymptomatic cases are often referred to as “superspreaders” as they’re typically unaware they have the virus due to showing no symptoms, but that term might be misleading. Not all asymptomatic ones may develop the high viral load to become superspreaders, as this (important) phenomenon is still poorly understood. (see e.g. Pablo Beldomenico “Do superspreaders generate new superspreaders? A hypothesis to explain the propagation pattern of COVID-19” on May 10, 2020 in https://www.ijidonline.com/article/S1201-9712(20)30332-5/abstract)

IMHO, we do not know enough and the Western democratic nations are performing poorly to contain a contagious pathogen, to the detriment of their citizens. We need an international, global response which is based on science, sound concerning strategies and accurate numbers to base them on — and international cooperation, not accusation.

The case of the Diamond Princess

The cruise ship Diamond Princess arrived off the Japanese coast in early February with more than 3,700 passengers and crew members from more than 50 countries and regions. It was placed under quarantine on 4 February 2020 after authorities found that a passenger who got off the boat in Hong Kong during its voyage tested positive for the virus. On 20 January 2020, an 80-year-old passenger from Hong Kong embarked in Yokohama, sailed one segment of the itinerary, and disembarked in Hong Kong on 25 January. He visited a local Hong Kong hospital, six days after leaving the ship, where he later tested positive for COVID-19 on 1 February. On its next voyage, 4 February, the ship was in Japanese waters when 10 passengers were diagnosed with COVID-19 during the unfolding of the 2019–20 coronavirus outbreak .

The infections included at least 138 from India (including 132 crew and 6 passengers), 35 Filipinos, 32 Canadians, 24 Australians, 13 Americans, 4 Indonesians, 4 Malaysians, and 2 Britons (see also https://www.theguardian.com/uk-news/2020/feb/18/britain-to-evacuate-citizens-from-coronavirus-hit-cruise-ship-diamond-princess). Home countries arranged to evacuate their citizens and quarantine them further in their own countries. As of 1 March, all on board including the crew and the captain had disembarked.

Officials kept finding new infections among the passengers and crew members and transporting them to Japanese hospitals, while others have been told to stay inside their individual cabins during the 14-day quarantine period. Japan’s efforts to control the viral infections on the vessel have prompted international concern. https://www.channelnewsasia.com/news/asia/coronavirus-covid-19-japan-cruise-ship-diamond-princess-12439564. The Japanese government was arranging special embarkation procedures for US citizens taking the chartered flight, an official said, adding that “a certain number” of other countries have also shown interest in similar evacuation measures.

While some Americans on the ship have urged their government to extract them from the boat, others on board criticised the plan. “Incredibly disappointed that the US Government has decided to throw a monkey wrench into the quarantine we have maintained here on board the Diamond Princess,” tweeted Matt Smith, an American lawyer. “The US Government … wants to take us off without testing, fly us back to the US with a bunch of other untested people, and then stick us in 2 more weeks of quarantine? How does that make any sense at all?” https://www.channelnewsasia.com/news/asia/covid19-coronavirus-us-evacuate-diamond-princess-japan-12438432

With 3,700 passengers and crew on board, the Diamond Princess was at that point with the highest rate of coronavirus infection in the world outside of China.

It also makes up for a very interesting study of asymptomatic cases and repetitive testing of a quarantined population. A paper by Mizumoto et al. accepted on 12/03/2020 and published in Eurosurveillance (Europe’s journal on infectious disease surveillance, epidemiology, prevention and control) accounts for the ratio of symptomatic vs. asymptomatic cases there. The result of the team around comes with a lot of cautious epidemiological math, ending at 17,9% asymptomatic cases accounted for. In an earlier version they reported the following progression of cumulative data over 7 days (13/02/2020–20/02/2020) https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.10.2000180 :

“Of the 634 confirmed cases, a total of 306 and 328 were reported to be symptomatic and asymptomatic, respectively. The proportion of asymptomatic individuals appears to be 16.1% (35/218) before 13 February, 25.6% (73/285) on 15 February, 31.2% (111/355) on 16 February, 39.9% (181/454) on 17 February, 45.4% (246/542) on 18 February, 50.6% (314/621) on 19 February and 50.5% (320/634) on 20 February.“

As of 23 March 2020, at least 761 out of the 3,711 passengers and crew had tested positive for the virus. The asymptomatic ones were getting tested repetitively, some became symptomatic, some stayed without symptoms, despite being positively tested. This dynamic may be a bit difficult to envision, so I add here also the table of cumulative counts, to clear the picture a bit:

Mizumoto Kenji, Kagaya Katsushi, Zarebski Alexander, Chowell Gerardo. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill. 2020;25(10):pii=2000180. https://doi.org/10.2807/1560-7917.ES.2020.25.10.2000180

Their estimated asymptomatic proportion they conclude at 17.9% (95%CrI: 15.5–20.2%), which overlaps in their view with a recently derived estimate of 30.8% from data of Japanese citizens evacuated from Wuhan (the study cited above). The team around Mizumoto notes clearly:

Considering the reported similarity in viral loads between asymptomatic and symptomatic patients and that transmission of SARS-CoV-2 by asymptomatic or paucisymptomatic cases may be possible, even though there is no clear evidence as yet of asymptomatic transmission, the relatively high proportion of asymptomatic infections could have public health implications.

This reported “similarity of virus loads” another important part of the puzzle can be found in Zhou et al.: “The viral load that was detected in the asymptomatic patient was similar to that in the symptomatic patients, which suggests the transmission potential of asymptomatic or minimally symptomatic patients. These findings are in concordance with reports that transmission may occur early in the course of infection5 and suggest that case detection and isolation may require strategies different from those required for the control of SARS”. Look their whole account up at: Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med. 2020;41(2):NEJMc2001737. https://doi.org/10.1056/NEJMc2001737 PMID: 32074444

That patients without symptoms can be very well contagious has been also assessed in this large study of “Clinical characteristics of 2019 novel coronavirus infection in China” by Guan et al. published in the New England Journal of Medicine doi: https://doi.org/10.1101/2020.02.06.20020974 on 09/02/2020 already. The full text can be downloaded here: https://www.medrxiv.org/content/10.1101/2020.02.06.20020974v1.full.pdf

The Japanese Ministry of Health, Labour and Welfare has stated on it’s official website concerning the Diamond Princess case that of 508 patients who have been discharged in Japan, 262 are symptomatic and 246 are asymptomatic, which excludes those returning on charter flights. https://www.mhlw.go.jp/stf/newpage_10251.html (with google translation). So, the Japanese authorities count 48% of asymptomatic cases in the remaining positive passengers of the Diamond Princess after 40 days since putting the ship under quarantine on the 4th of February. In domestic cases they report in a 717 patient example that asymptomatic pathogen holders were found in 88 cases — that would be ca. 12%.

UPDATE: The case of the Shackleton Cruise from Argentina

In the footsteps of Ernest Shackleton, but with Covid-19 on board an unnamed ship left in mid-March from Argentina for a planned 21-day cruise of the Antarctic, along a similar route taken by explorer Sir Ernest Shackleton in the early 1900s. The ship became the center of a study where the authors were part of the passengers and the ship physician, too. Of the 217 passengers and crew on board, 128 tested positive for the virus and of those, 104 patients — 81 per cent — did not have symptoms. (see the study of Ing, Cox & Green in Thorax Journal on 27/05/2020 https://thorax.bmj.com/content/early/2020/05/27/thoraxjnl-2020-215091)

The first recorded fever on board the ship was on day eight and the study authors said from that point all passengers were confined to their cabins and surgical masks were issued, while full personal protective equipment was used for any contact with any patients with a fever. Eight people had to be medically evacuated from the ship and the authors said there had been one death to date. Their study accounts for 19% (24) being symptomatic; 6.2% (8) requiring medical evacuation; 3.1% (4) intubated and ventilated and the mortality at 0.8% (1). That means, in this case there were 4,3x more asymptomatic cases than symptomatic ones. Again, the dark numbers seem to cause less perceived damage, but if the ratio of symptomatic/asymptomatic holds up over time, we need to plan and account for them in mitigation strategies and not just close our eyes. Having a spread of Covid-19 on board AFTER symptom screenings before departure also suggests the simple conclusion that screening for symptoms or recent travel history is not enough to prevent an outbreak…

UPDATE: Cluster of 70 positive through asymptomatic spread of 1 returning traveller

Heilongjiang Province, China, had not reported a new COVID-19 diagnosis since March 11, 2020. On April 9, SARS-CoV-2 was diagnosed in 4 patients. By April 22, >71 persons had been infected. The likely origin of this cluster is an imported case from an asymptomatic traveler. Patient A0 turned out to be a woman travelling back from the USA, being immediately quarantined and having no contact with the public environment other than through using the elevator, alone. This case study published as a letter of research on CDC.com seems to be a rare mix of returning from abroad, asymptomatic spread through surfaces and a large resulting cluster, where other factors can be ruled out step by step. See Liu J, Huang J, Xiang D. Large SARS-CoV-2 outbreak caused by asymptomatic traveler, China. Emerg Infect Dis. 2020 Sep [date cited]. https://doi.org/10.3201/eid2609.201798 published on 30/06/2020.

Conclusions

  1. WEAR MASKS when you are outside and learn how to properly wear them and take them on and off. Also home-made ones do prevent the spread of droplets to a certain degree and are better than nothing until better masks are more widely available — so you save others from your breath and cough even if you are without symptoms.
  2. TAKE ASYMPTOMATIC SPREAD SERIOUSLY in Covid-19. Measuring temperature is not enough. Contaminated surfaces may come from asymptomatic people as well, and may add up in hot spots and cluster areas. Wash your hands often. Use a tooth-pick or the pointy end of your key to press buttons, if possible (a strategy I learned from Hong Kong).
  3. Reliable estimates of the reproduction number and the death risk associated with COVID-19 are crucially needed to guide public health policy. The dark numbers or “asymptomatic proportion” , which is broadly defined as the proportion of asymptomatic infections among all the infections of the disease may be a crucial and useful quantity to gauge the true burden of the disease and better interpret estimates of the transmission potential. The range of cases overseen here indicate a reasonable estimate of 12–81% of the real infection cases staying largely asymptomatic. Asymptomatic or minimally symptomatic patients also do expose a viral load comparable to cases with symptoms (fever, throat ache, cough), so there is no scientific reason not to take these findings seriously. How much they prove to be contagious and infect other people — is there a reliable R0 for asymptomatic cases estimated or validated–remains in the dark also till the end of May even though there were large serological test with representative groups being proposed (and partly conducted). It is still fair to say that the dark numbers might affect the spread of the SARS-Cov-2 virus and may pose a threat as a residue of new clusters, now and when official numbers dwindle.
  4. Dropping the guard might lead to a surge of infected, as many are not aware of being actually contagious and might spread the virus because of bad compliance or “disaster fatigue”. This experiment we see happing now (14/04/2020) as governments are competing with each other who might be first to get back to an “acclaimed” normalcy. Let’s watch Austria and the Veneto region in which I live, where the governor Luca Zaia has just eased the measures. The results we will see in positively tested cases in about 2 weeks…
  5. LET’S WATCH CLOSELY what happens in China after the lockdown — and what in the USA and Brasil with way higher numbers. On 23/03/2020 Caixin Global reports (see https://www.caixinglobal.com/2020-03-23/despite-official-figures-wuhan-continues-to-find-new-asymptomatic-covid-19-cases-daily-101532880.html ) that despite official figures proclaiming that no new domestic Covid-19 cases occurred, authorities continue to register asymptomatic cases, sometimes “a dozen a day”.

According to a member of the infectious disease prevention and control team in Wuhan, every day the city continues to record “several or more than a dozen asymptomatic infected individuals,” which are people that have tested positive for Covid-19, but do not feel ill and are excluded from published numbers.

The infectious disease prevention and control team has stayed behind, after Hubei’s provincial Covid-19 task force was ordered to remain.

5. More (validated) tests please, in the millions. Now. Not in 6 months. And make proper random tests if test capacity allows only for that, with representative groups to find the amount if real infected in the population and how many of the had symptoms and how many are immune…and for how long. IgM, IgG and other serological laboratory blood data may help us to understand how many people came into contact for real and it may help us to understand the proportion of deaths and severe cases better.

If we forget the asymptomatic ones out there, we will have a hard time to get rid of this SARS-Cov-2 / Covid-19 pandemic. With the extreme case of 6–96% of the really infected people (or up to 16x) of the symptomatic ones, maybe moderately between 2x and 5x in the reality of the demographics we will face a long time of recurrent clusters of infections and “necessary” lockdowns if we ignore that. All this could have gotten avoided in first place by due diligence, so we shall not put our heads in the ground and think this is simply over — it may only take 2–3 months to come back. The focus on “opening up” due to economic pressure distracts from the epidemiology of Sars-Cov-2 and the role played by cases of infection which are not even officially “sick”. This may turn out to be a big mistake mid-term and long-term…

This article has been also published first as a Facebook note on 23/03/2020 in my FB profile https://www.facebook.com/notes/herwig-egon-casadoro-kopp/dark-numbers-rule/10158103025998834/

& on tropicofchoice.com on 24/03/2020 http://www.tropicofchoice.com/dark-numbers-rule/

It got amended and updated on the 14/04/2020, on 29/05/2020, 15/06/2020 and 16/07/2020.

All spelling mistakes still lingering or erroneous deductions shall be solemnly attributed to me — I am happily discussing them and grateful for constructive feedback leading to corrections or other new considerations. Make deductions or assessments at your own risk.

Ex-brain researcher, speaker & narrative interaction designer researching the reality of fiction

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