key: cord-262104-oig3qrr7
authors: Brüssow, Harald
title: COVID‐19: Test, Trace and Isolate‐New Epidemiological Data
date: 2020-06-08
journal: Environ Microbiol
DOI: 10.1111/1462-2920.15118
sha: 
doc_id: 262104
cord_uid: oig3qrr7

In the absence of an efficient drug treatment or a vaccine, the control of the COVID‐19 pandemic relies on classic infection control measures. Since these means are socially disruptive and come with substantial economic loss for societies, a better knowledge of the epidemiology of the new coronavirus epidemic is crucial to achieve control at a sustainable cost, and within tolerable restrictions of civil rights. This article is protected by copyright. All rights reserved.

comprising 10'800 participants (Gudbjartsson et al., 2020) . Very similar information was reported in data describing household transmission in Wuhan, where children showed a 4% infection rate compared with 17% in adults. . Likewise, in a study from Hunan children had a threefold lower infection risk than adults . In contrast, the infection risk in children from Shenzhen, China was similar to that in adults (Bi et al., 2020) . However, all studies concur that disease in children is generally mild, if not asymptomatic. Asymptomatic cases raise problems for contact tracing and containment, but it is currently not clear to what extent infected children transmit the disease. Three asymptomatic SARS-CoV-2-positive adolescents showed transmission to family members (Liao et al., 2020) while data for transmission from children are still absent.

One special problem should still be mentioned in this context: In Italy, pediatric hospitalization decreased substantially during the COVID-19 epidemic. When the general population avoids hospitals for fear of infection, it can have a negative health impact. An increased number of deaths occurred in Italy due to delayed arrival of children in hospitals, while no child died from COVID-19 in Italy (Lazzerini et al., 2020) . The fear of hospitals has also been responsible for a deficit in the treatment against stroke in adults in the US (Kansagra et al., 2020) .

The statistics for the COVID-19 epidemic have shown that the older population has suffered the greatest loss of life, and that nursing homes have been hotspots for transmission. Two detailed studies from the US document these given facts. At the end of February 2020, a cluster of 167 epidemiologically linked COVID-19 cases were reported in several long-term care facilities in Washington State. Of those, 144 cases were residents (median age 83 y), 55% of them were hospitalized, and 33% died. In comparison only 16 cases had been visitors, 50% of whom were hospitalized, but none died. Further 50 cases were among the health care personnel, of whom only 6% were hospitalized, but again none died. Factors favoring the outbreak were: health care personnel who showed up to work with symptoms; some of the personnel worked at more than one facility; and some residents were transferred between facilities. In the early stages of the epidemic, contributing factors to this outbreak were: an unawareness of the risk; a lack of diagnostic tests; and inadequate personal protection equipment (McMichael et al., 2020) .

Currently, 1.3 million US Americans reside in nursing homes. One in ten of >1'300 accredited nursing facilities reported COVID-19 cases. An epidemiological survey in such a facility demonstrated the extent of the problem: the first infection in this nursing home was introduced by a symptomatic nurse, and then a week later the first resident tested positive. A further 5 days later, half of the residents from this unit tested positive for viral RNA. During the following 2 weeks, 30 to70% of the residents in other units of this home became infected, along with 19% of the staff. Notably, more than half of the residents were asymptomatic when they tested positive for viral RNA. Four days later, 89% of them had developed symptoms. The rest remained asymptomatic. Mortality was high at 26%. Importantly, asymptomatic, pre-symptomatic, and symptomatic residents did not differ with respect to viral load and infectious virus release. All viruses showed identical genome sequences

Guangdong cases. In Guangdong province of China, all return visitors from Wuhan/Hubei province, their contacts, and all of the local hospitalized patients were tested for viral RNA. 1.6 million tests were used to identify 1'400 SARS-CoV-2-positive cases; 1000 patients had had exposure to infected people from Hubei. Half of the local transmissions occurred within households. By mid-February, the local spread was controlled, but in March new cases were imported from abroad. Sputum samples showed the highest viral titers, followed by oropharynx, stool, and finally nasopharynx samples. Critical and severe cases showed higher viral titers than moderate and mild cases, but the differences were small. Viruses from 53 patients were sequenced and compared with 177 SARS-CoV-2 sequences deposited in the database. Single nucleotide polymorphism (SNPs) were detected at 97 nucleotide positions scattered through the viral genome; 77 variant sites were only seen in a single virus isolate. On a phylogenetic tree, the Guangdong sequences were interspersed between the viral sequences from Wuhan and those isolated abroad, documenting a recent, single source outbreak of a virus showing a low mutation rate (Lu et al., 2020a) .

USA west-to-east spread. The first case of COVID-19 in the US was reported on Jan 19 at the northwest coast of Washington State and was imported from China. From March 1 to 19 the number of cases in the US increased from 70 to 13'000. Epidemiologists investigated the first nine COVID-19 cases on the East coast (Connecticut) that were observed in mid-March with genome sequencing. Only one sequence exactly matched the viral sequences from China, but the patient had not traveled to China. The viral sequences from seven further patients, clustered with a large US clade known from Washington State, documented a rapid west-to-east national spread of the novel coronavirus in the US. International air travel restrictions had no, or low, impact on the epidemic spread in the US. The viral genome was rooted in a single ancestor coronavirus in Wuhan by fewer than 10 mutations, and it had accumulated about 2 nucleotide changes per month during its spread across the US, which is a low mutation rate for a 30'000 nucleotide long viral RNA genome. With the portable Oxford Nanopore Technologies MinION platform, viral genomes were sequenced within 14 hours after having received the sample, theoretically allowing near real-time molecular epidemiology of the epidemic spread (Fauver et al., 2020) .

China. In Wuhan, 105 index cases of patients suffering from moderate COVID-19 symptoms (fever, cough, fatigue) were investigated for secondary transmission to 392 household contacts. The average household size was 4 persons. The index case persons remained at home for a documented number of days before seeking medical advice. In total, 64 contacts (16%) were infected, 9 without symptoms, and the rest experienced moderate disease. The time lapse between primary and secondary infections was 6 days. The transmission probability was age-dependent: it was 4% in children and 17% in adults. The highest transmission rate was seen in 50 to 60 year-olds, but not in >60 year-old household members. Spouses experienced a 28% infection transmission rate. When the index case was quarantined directly after symptom onset, transmission rate was 0% .

In Shenzhen, 391 cases were recorded, 77% of which were detected through the surveillance of symptoms. Most cases were mild (26%) or moderate (65%). Only 9% of infections were associated with severe disease, which correlated with male sex and older age; 3 patients died. The researchers identified 1'281 close contacts for the index cases; 8% of these had become infected. An increase to 16% in the rate of infection was seen in those who lived or traveled with index case persons. Interestingly, infection risk was comparable for all age groups ranging from 0 to 70 y old. However, half of the children showed no fever, and severe infections were rare in people under the age of 40. Notably, 80% of secondary infections were traced to only 9% of the index case persons (Bi et al., 2020) suggesting an important role of "super-spreaders" in infection transmission. It would be helpful for public health if characteristic traits of super-spreaders were known.

Adding viral-specific IgG antibody tests to the toolbox of COVID-19 have allowed the connection between three previously separated infections clusters in Singapore. An infected traveler from Wuhan attended a church meeting, thereby infecting a secondary person (case X), who transmitted the virus to another subject during a family gathering, who then transmitted the virus to a large number of people in a second church. Case X tested negative for viral RNA and represented the missing link between the events. Case X showed a strong serological response to SARS-CoV-2, then connecting the links in the chain (Yong et al., 2020) .

Iceland. From among 9000 high risk Icelanders (persons who were symptomatic, or had contact with infected persons, or who traveled to a high risk country) 13 % tested positive for SARS-CoV-2 RNA. Children under 10 years from that high risk group showed a 7% RNA detection rate compared with 14% in subjects older than 10 y. Before mid-March, travel exposure to Austria and Italy was a common denominator in the positive subjects. After mid-March, travel to UK was the biggest risk factor. In mid-March, a representative sample of 11'000 subjects from the general population of Iceland (360'000 inhabitants) was tested, and 0.8% tested positive for SARS-CoV-2 RNA. In April, another sample of 2000 subjects from the general population showed a similar rate of viral excreters. In the general population, males were more frequently virus-positive than females. The highest prevalence was seen in 40 y-old subjects, while no children under 10 y were infected. Five hundred viral genomes, isolated from infected Icelanders, were sequenced. The genomes were clustered into 42 distinct clades. During the early epidemic phase in Iceland, nearly all SARS-CoV-2 isolates belonged to the A2 clade which was also frequently found in central European populations. Viral genome sequencing identified networks of up to 14 linked infections. Transmission occurred in the early phase via international travel, but later via infection from family members (Gudbjartsson et al., 2020) .

Airborne: Cough, sneeze and speech. Australian engineers evaluated the literature about the reach of pathogen transmission by coughing and sneezing. The 1 to 2 meter rule has been set since the 1940s by photography, physical calculations, and through simulations. Distinct models (turbulent jets vs. puffs) have been used, but not all used appropriate parameters for humidity and temperature. It remains unclear which conditions apply to the human respiratory excretions when handling infected patients in a clinic (Bahl et al., 2020) . Newer high speed pictures of a coughing volunteer show a turbulent jet plume that extends over 0.5 meter (Tang and Settles, 2020) . High speed pictures of a sneezing volunteer revealed exhaled air, muco-salivary filaments and drops. The turbulent puff cloud disintegrated into droplets that settled within 1 to 2 m distance. Some droplets evaporate and become suspended in the puff and travel a room within a few minutes to land 6 to 8 m away from the sneezing person (Bourouiba, 2020) Speech generated droplets in front of the mouth increased with the loudness of the voice. Holding a cloth in front of the mouth suppressed the droplet detection (Anfinrud et al., 2020) .

A WHO communication led to a controversy saying that there is not enough evidence that SARS-CoV-2 transmission is airborne. WHO defines airborne transmission as being via aerosols as opposed to transmission by droplets. Since most COVID-19 transmission seems to occur through close contact, droplets have been considered to be the more likely vehicles. Whatever the exact transmission route by air, avoiding crowds, standing next to a person for too long, and increasing the rate of ventilation in closed rooms without air recirculation are reasonable precautions (Lewis, 2020) .

Physicians recommended face mask use, even when scientific evidence for its effectiveness is lacking, in comments to leading medical journals. Recent reviews have concluded that: no randomized trials with masks have been conducted; that the benefit of masks over no masks (but not of respirator masks over paper masks) was shown in an influenza epidemic in Australia; that some benefit of masks was seen when worn by symptomatic, but not by asymptomatic cases during an influenza epidemic; that no data exist which directly support the use of mask wearing by the public; that no significant effect was seen for household use of masks against influenza transmission. Therefore, WHO initially recommended masks only for symptomatic cases. CDC first advised against mask use by the public but have now changed their policy by recommending even self-made cloth masks for wide use. Harm (e.g. increase of CO 2 level under the mask) is low if not used by small children or elderly people with disabilities (Cheng et al., Greenhalgh et al., 2020) .

As assessed by viral RNA detection, air and surfaces in a Wuhan hospital were widely contaminated during the height of the epidemic in China. Contamination levels were greater on the intensive care unit ward than on the general ward. The transmission of SARS-CoV-2 might reach up to 4 meters distance. However, no medical staff in that particular hospital was infected. The authors admit two limitations of the study which prevent firm conclusions from being made. First, viral RNA detection does not mean infectious virus detection, and second, the minimum infectious dose of SARS-CoV-2 for humans is unknown . When reviewing the official recommendations, the consensus seems to be to use a respirator for high risk interventions which create aerosols in the ICU, and to use surgical masks on the general ward with low risk activities (Bahl et al., 2020) .

Singapore hospital. The environment of three COVID-19 patients from a ventilated hospital infection ward in Singapore was tested for viral RNA presence by RT-PCR. After routine cleaning of high touch areas and of the floor, no viral RNA was found in the air, on hospital room surfaces or on the personal protection equipment of the treating physician. Before routine cleaning, however, 16 of 20 room sites (table, chair, floor, window, toilet) and the shoe protection of a physician tested positive. Room air samples and hospital corridor floors were, however, negative for viral RNA. For infection control, regular room cleaning and handwashing were judged to be essential (Ong et al., 2020) .

PRIMIT study. It is more problematic to establish a control when a family member with mild infection remains at home. There is only one behavioral intervention study that has proved to reduce respiratory viral transmission within households, the PRIMIT germ defense study. The key interventions are web-based instructions about handwashing given to 10'000 intervention subjects in UK, but not to 10'000 controls. Infection transmission was reduced by 20% and infection severity was also reduced, albeit modestly (Little et al., 2015) . The rationale behind the idea was to reduce the viral load by which contacts are particularly exposed, such as through hand-to-eye contact, since the conjunctiva supports SARS-CoV-2 replication (Hui et al., 2020; Little et al., 2020) .

In Italy, the epidemic started in Lombardy and Veneto. Lombardy strengthened their hospital capacity and increased ICU beds, while Veneto opted for strict containment and mass testing in 4% of the population. Lombardy experienced 47'000 more cases than Veneto and also had a much higher crude case fatality rate (18% vs 6%). The higher death rate is probably explained by the delayed public health response (Odone et al., 2020) as also seen in the US (Anonymus, 2020) .

The Swedish government had recommended a number of trust based measures (social distancing from old people, handwashing, home office, travel reduction), but refrained from closing borders, schools, restaurants and bars, partly because the Swedish law does not allow lockdowns. The case reduction of seasonal influenza and Norwalk diarrhea provided documented effectivity of the measures taken (Paterlini, 2020) . However, compared with neighboring Finland and Norway, Sweden experienced a tenfold higher number of deaths for a 1.5 fold larger population, but the absolute numbers are still small (3700 vs. 300 for Sweden and Finland, respectively, May 18).

In the US, the individual states and CDC have many legal options for quarantine (for the segregation of exposed people) and isolation (separation of infected people from the general population) in such cases as with SARS. The establishment of broad sanitary cordons in which entire geographical areas are quarantined (as has happened in Wuhan) will raise constitutional questions in the US. The US recommendations say that patients who show mild symptoms should stay home and notify their employer electronically. Low-wage workers cannot afford to stay off work, but the US senate is in the process of establishing bills for paid sick leave and unemployment insurance (Parmet and Sinha, 2020) .

Kong. The control measures that stopped the epidemic locally have included: intense infection surveillance of incoming travelers; isolation of COVID-19 cases in hospitals; contact tracing and quarantine in holiday camps; and school closure but no lock-down, thus preventing the crisis from having a negative economic impact. A total of 715 cases were confirmed, half imported, and the rest locally transmitted with a reproduction number that quickly decreased to values around 1; and 13% of virus-positive subjects were asymptomatic. The control measures also stopped an ongoing seasonal influenza epidemic. Surveys showed that the population agreed to participate in the measures. They kept social distancing and made behavioral changes (99% wearing masks outside house, 93% increased hand hygiene, 83% staying at home as much as possible). The study could not differentiate the impact of each individual measure. Unfortunately the full effect of school closure is still unknown because the susceptibility of children for COVID-19 and their capacity to transmit the infection has not yet been established .

China has contained the COVID-19 epidemic through a combination of different measures including drastic ones. An international team of epidemiologists developed a computer model that described the dynamics of the epidemic and tested the impact of the different containment measures by using computer simulations. Without any intervention, a 100-fold higher number of cases would have occurred in China, resulting in over 10 million cases. Without travel restrictions, the epidemic would have expanded more widely over the western provinces. Early detection and isolation of patients reduced the number of cases by 5fold, while social distancing and contact reduction led to a 2.6-fold reduction. However, without contact reduction, the epidemic would have, over time, increased exponentially across the regions. Initiating the intervention one week earlier would have decreased the number of cases by 66% or, if done one week later the number of cases might have increased by 3-fold. A delay of 2 or 3 weeks would have increased cases by 7-and 18-fold, respectively. Lifting travel restrictions will result in a new rise in case numbers, but even moderate levels of social distancing could keep this increase in check. Partial maintenance of NPI may prevent, or at least delay, the arrival of second wave infections (Lai et al., 2020) .

Contact surveys were conducted in Wuhan and Shanghai during the height of the COVID-19 epidemic in China. Before the epidemic, people reported between 15-18 contacts (two-way conversations, physical contact) per day. This number was reduced to 2 during the containment period. Contact reduction was most significant for school-age children who, before the intervention, reported the greatest numbers of contacts out of all of the age groups, followed by adults at the workplace. During containment, contacts were mainly within families (80-95%). The survey was consistent with data from inner city mobility.

All contacts of patients in Hunan province were placed under medical observation and tested for excretion of viral RNA. From these contact data it was deduced that children (<14 y) had an infection rate that was only a third as high as adults (15-65y), while older individuals had a 50% higher infection rate than young adults. Based on these data and on a mathematical infection model, the authors concluded that social distancing alone is sufficient to control COVID-19 spread. Proactive school closure alone cannot interrupt transmission but can reduce the peak incidence of the disease by half, and it can delay the epidemic ). These are model simulations based on assumptions on infection transmission by children for which only few data are currently available. The reopening of schools in several countries will hopefully settle some questions with observational data.

Psychologists argue that contact-seeking is a basic human response to danger. This inclination takes over when an invisible infection threat is perceived. This instinct is only opposed by disgust when infected persons show appalling clinical signs which is not the case for SARS-CoV-2 infected subjects in pre-symptomatic or asymptomatic state. It will be increasingly difficult for health authorities to impose social distancing, as proven by the street demonstrations against containment measures in the US and in European countries by differently motivated opposition groups. The authors argue that the increased use of the internet as a substitute for contact can become an important public health tool to achieve physical distancing without social distancing (Dezecache et al., 2020) .

By May 18, the Johns Hopkins University registered 4.7 mio cases worldwide. The lion's share is from the US with 1.4 mio cases, compared with 84'000 cases reported by China. One should interpret these data with caution. The definition for a confirmed case of COVID-19 was changed five times in China, which accounts for the increase in knowledge about the epidemic. Scientists from the WHO Collaboration Center in Hong Kong calculated that when the fifth version is applied, the total number of cases in China would increase from 55'000 to 230'000, but the transmission patterns in mainland China would not change . The case number also depends on the intensity of viral testing and the capacity of the public health system to report the number of cases.

With nearly 90 '000 deaths, the US number greatly surpasses the 4'600 deaths reported in China. It is still difficult to assess the morbidity and mortality impact of the COVID-19 pandemic on the population. Even mortality rate is not a clear figure since it is reported differently in different countries. While death is a clear diagnosis, the cause of death isn't. It might not be evident whether somebody died with or from COVID-19, particularly in nursing homes. Some countries attribute death to COVID-19 if the virus was present at death. Others attribute each death in nursing homes to COVID-19 during the height of the epidemic -as was done in Belgium, which explains its high mortality data. Many deaths occurred while people also had underlying health problems (comorbidities), therefore they were already at increased risk of death.

An international consortium of demographers called for the publication of excess mortality data. By comparing mortality statistics for a given epidemic period with a corresponding time period during previous years without that epidemic, the absolute impact of an infection can be assessed. Such data are still largely lacking in the literature. Excess mortality rates should best be calculated for both sexes and for each 5-y age range separately (Leon et al., 2020) . First data have just now been reported: In March/April the care sector of England and Wales alone has seen 20'000 excess deaths over the figures of previous years. COVID-19 deaths at care homes were three times as high as COVID-19 deaths in hospitals (Burki, 2020) .

Excess mortality calculations have been done globally for seasonal influenza, arriving at 300'000 to 600'000 influenza-associated deaths occurring annually (Iuliano et al., 2018) . While the majority of influenza mortality applies to elderly people, the death rate is also substantial for children at an estimated 34'000 deaths in 2018 . In comparison, the global death toll of COVID-19 is now 315'000 (status May 18). A direct comparison of these two figures is difficult for two reasons: death levels are affected by vaccination campaigns against seasonal influenza and by strict containment measures for COVID-19. It seems plausible that without any containment measures COVID-19 mortality would surpass greatly the number of deaths from seasonal influenza. The presumption that the COVID-19 mortality is comparable to that of seasonal influenza deaths is fundamentally flawed because it compares numbers which are obtained by different methods. The death rate for COVID-19, which has just crossed the 100'000 figure in the US, is an actual count of dead patients. In contrast, the 23'000 to 61'000 annual deaths from seasonal influenza quoted after influenza epidemics in the US are estimates by the CDC of influenza deaths based on calculations from models. The death counts actually reported to US health authorities ranged from 3'400 to 15'000 deaths per year during an influenza epidemic in the US. Expressed as deaths per peak week, influenza claimed a maximum 1'616 deaths per week, while COVID-19 took about 15'000 lives per week at its peak in the US (Faust and del Rio, 2020) .

Wuhan. An international consortium of epidemiologists has estimated that 66'000 people were infected in Wuhan and that 2800 have died; 70% were infected through household contact, 25% through public contact, and 5% in hospitals. From a peak number of 2000 new infections, Wuhan currently has 10 or fewer new infections per day. Safe strategies are now needed for the exit from lockdown measures. When lifting the lockdown to a 100% pre-quarantine social contact level, a computer model showed that a 95% face mask wearing would be needed to ensure a complete elimination of infections. In contrast, with only 50 % face mask use and a lifting date of strict measures before April 25 to pre-quarantine level, the conditions in this model would lead to a major second wave of infection. Maintaining a contact rate below pre-quarantine level combined with a high percentage of face mask wearing is essential while now the restrictions have been lifted in Wuhan-at least until a vaccine becomes available. However, face mask provision for such large populations represents logistical challenges and must not cause a shortage of protective gear for health personnel (Zhang et al., 2020a) .

In mainland China, 13'400 confirmed cases and 120 deaths were reported by March 18. In Beijing and Shenzhen, most cases have been imported from Wuhan and the reproduction number R remained below 1.0. In Shanghai and Wenzhou, local cases dominated but R rose to greater than 1 for only one January week. Case fatality was 1% compared with 6% in Hubei. Relaxing the restrictions could lead to a second wave of exponential infection from imported cases in a nonimmune, susceptible population. Maximizing economic productivity under the < 1 constraint can, according to this study, only be possible with a real time prevalence determination of new infections through extensive testing .

Other epidemiologists working on outbreak data from mainland China observed a sub-exponential increase of cases from the beginning, instead of an expected exponential growth for an unconstrained epidemic. Model calculations showed that the containment measures (the quarantine of exposed, and the isolation of infected persons) which depleted the number of susceptible individuals for the virus, reproduced the actually observed case development. Similar strategies are recommended in the event of a future outbreak (Maier and Brockmann, 2020) .

Harvard model. Epidemiologists from Harvard University derived projections from model calculations about the future dynamics of the COVID-19 epidemic. When anticipating short term immunity (as observed for seasonal common cold coronaviruses), they predict annual winter epidemics for SARS-CoV-2. With intermediate levels of immunity persistence, epidemics would become biannual. Long-term immunity (as in the case of SARS-CoV) would lead to the extinction of the virus, even in the absence of social distancing. They also calculated that it needed 20 weeks of social distancing to reduce the peak number of infected persons. If the reproduction of the virus is reduced by more than 60% through lockdowns, the infection peak is predicted to shift to the next winter season with high numbers because no herd immunity has been achieved (Kissler et al., 2020) .

A central concept of epidemiology is herd immunity; the percentage of persons with protective immunity needed in a population to stop the propagation of an infectious agent. When this threshold is crossed, the remaining susceptible persons are protected from infection. The threshold level depends on the "force" of the infectious agent which is expressed by the basic reproduction number R 0 ,which is defined as the number of secondary infections caused by an index case. In infection modeling, herd immunity threshold and R 0 are linked by a simple mathematical function. SARS-CoV-2 has a higher R 0 "infectious force" than influenza virus, but a much lower one than "flying infections" such as chickenpox or measles. It is anticipated that a population needs a herd immunity of 50 to 80 % protected people to stop the COVID-19 epidemic.

The initial strategy of the UK government was to let the epidemic roll over the country to achieve this herd immunity, in contrast to containment policies which prevent exposure, but which also prevent immunity development in the population. This strategy has theoretical advantages (fewer economic losses when a lockdown is avoided, and a protected population in the event that no vaccine becomes available). However, it comes at a cost. If you allow, let's say, 60% of the population to get infected, you can calculate the cost of this strategy with the help of the infection fatality rate (IFR). In contrast to the case fatality rate (CFR) which expresses the number of deaths per clinically ill patients (which varies from 1.4% to 15% for COVID-19), IFR is the number of deaths per infected individual. The number is, of course, lower than CRF. While we know, approximatively, the number of COVID-19 deaths and COVID-19 cases, we do not definitively know the number of infected persons, since this would require large and systematic seroprevalence studies, but which are lacking. Current estimates suggest 0.6% as a realistic approximation for IFR. With that figure, one can calculate that achieving herd immunity through natural infection with SARS-CoV-2 would cost the lives of 150'000 UK citizen or more than 1'000'000 US citizens. This death toll was considered as too high by the UK government, which then changed strategy by declaring a late containment strategy (Randolphe and Barreiro, 2020) . Delays in imposing containment measures were predicted to lead to 10-fold or higher number of cases and fatalities. This prediction might explain why the US and UK have such high case and death statistics in international comparison.

Mobile phone technology. Epidemiologists from the UK and US have developed a real-time datacapture platform applicable for mobile phone use for the self-guided collection of population-level data (COPE consortium). The app queries location, age, health risk factors and asks daily for new symptoms and diagnostic test results. A test run with 1.6 million users in UK showed that the most common symptoms were fatigue and cough. Anosmia (loss of smell) appeared as a strong predictor of COVID-19, while fever was not a diagnostic criterion unless combined with other symptoms. The reported symptoms predicted that there would be changes in the number of cases as indeed reported from health authorities 5 to 7 days later. The tool will be important for a controlled safe exit from confinement measures. Also, long-term effects of the disease, and the impact of the COVID-19 epidemic on social relations, mental health, and financial outcome can be evaluated with this tool. Machine learning could also reveal new disease manifestations of the epidemic (Drew et al., 2020) .

Anosmia is an interesting symptom. A preliminary evaluation of a COVID-19 Symptom Tracker smartphone app from UK users showed that the loss of smell was reported by 59 % of people with respiratory infection who tested positive for SARS-CoV-2, compared with 18% of respiratory patients who tested negative. Clinical criteria which allow a diagnosis of COVID-19 without a viral RNA test would be welcome for mass screening and telemedicine in an epidemic situation. French physicians have also reported that many COVID-19 patients reported loss of smell and loss of taste, without nasal congestion. When these criteria were combined in a retrospective questionnaire this combination of signs had a sensitivity of 42% and a specificity of 95% for detecting COVID-19 patients (Bénézit et al., 2020) . These observations are not surprising since the highest expression level of the SARS-CoV-2 receptor ACE-2 was shown in the respiratory tract, more specifically in the nasal epithelia. US physicians even suspected that SARS-CoV-2 might, in addition to the respiratory and alimentary tract, also infect cranial nerves (i.e. being neurotropic) which potentially explains the observation of neurological signs in 9 % of COVID-19 patients (Chu et al., 2020) .

Seroprevalence studies. Antibody tests are an important tool in a staggered release of population groups out of lockdowns because such tests identify people who have been exposed to the infection and who are potentially immune to infection. So far, only preliminary data became available from 3'300 volunteers from Santa Barbara county in California. One out of 66 (1.5%) showed antibodies to SARS-CoV-2. This number is 50-fold higher than the number of the official case count was for this area in early April. In a preliminary survey in Geneva, less than 5 % of a population sample showed viral-specific antibodies in preliminary surveys. In a town with 12'000 inhabitants in Germany, 500 people were antibody tested following carnival parties and an infection rate of 15% was determined.

These datasets cannot be extrapolated to the population at large. In addition, the antibody tests were only validated with a small set of positive and negative test samples, raising concerns about the reliability of the results (Mallapaty, 2020; Sood et al., 2020) . The next challenge will be the acquisition of reliable antibody data for representative samples from entire populations.

The COVID-19 epidemic continues to challenge our societies by its toll in deaths, by the disruption of social life; by its disastrous impact on the world economy; by increasing the debt of many nations; by endangering the survival of many industries; and by reversing the worldwide trend for poverty relief. For microbiologists, the COVID-19 crisis has also revealed shortcomings in the public health sector, particularly in that of countries which were exemplary in this field during past decades.

In the US, the COVID-19 epidemic has taken more lives in one month than over 8 years during the Vietnam War. With more than 1.7 million cases, and more than 100'000 deaths, the "America first" slogan has become sadly ironic in the context of COVID-19. An article in the leading US medical journal, The New England Journal of Medicine, attributes this calamity to insufficient diagnostic testing caused by the delivery of faulty tests by CDC; non-approval through the FDA of working tests by WHO resulting in a delayed start of viral detection activities; and then followed then by a shortage of test reagents. Public health workers were therefore blind to the unfolding of the US epidemic and unable to design efficient containment measures, short of a lockdown. Epidemiologists were left without population data for modelling the epidemic in the US at a moment when the country started reopening economic and public activity. In comparison with other countries the US has tragically "failed the test". In the words of this article "The US once a leader, seem oddly lost" (Schneider, 2020) . An editorial in the leading British medical research journal, The Lancet, comes to the same conclusion: The CDC, once a pillar and international reference for combating diseases worldwide, instrumental in eradicating smallpox and coping with AIDS or Ebola, has lost its technical competence and public trust due to contradictory scientific messages and the undermining of trust in scientific evidence by the current US administration. According to the Lancet editors, the "US Administration is obsessed with magic bullets-vaccines, new drugs-while only basic public health principles, like test, trace, and isolate, will see the emergency brought to an end" (The Lancet, 2020). The situation is not better in the UK, once also renowned for its excellent public health research, particularly in the field of respiratory infections (remember the Common Cold research unit). At the end of May, the UK directly follows the US in the international mortality ranking list with more than 38'000 COVID-19 deaths. The late onset of large scale testing, the lack of personal protective equipment, and a delayed introduction of containment measures have certainly contributed to this high death toll.

A correspondent to The Lancet deplores that the situation in Europe was no better with respect to the lack of a coordinated response to the pandemic. The European Center for Disease Prevention and Control (ECDC), which was established in 2004 to create a complement to the US CDC, failed to become a hub in Europe of knowledge for COVID-19 and a coordination center for Europe-wide epidemic counter-strategies. ECDC is underfunded (CDC in 2020: 8 billion $, ECD 60 million $) and understaffed (CDC: 10'800, ECDC: 270 employees). An emergency structure for a pandemic was not set up, and ECDC played essentially no role in pandemic crisis management, which was done according to EU laws by national organizations without any European coordination (Jordana and Triviño-Salazar, 2020) . Even the city-state of Singapore, where the early handling of the COVID-19 was lauded as exemplary public health action, had "blind spots" on their screen in overlooking the miserable living conditions of migrant workers that became hotspots of COVID-19 transmission. Of special global health concern are refugee camps from Bangladesh to Europe. A refugee camp on Lesvos/ Greece has just one water tap per 1300 residents, making efficient handwashing an impossible mission (Newland, 2020) . Governments plan to spend billions on rescuing what they consider to be essential national industries. It will be important that they also find the money needed for COVID-19 containment among migrant workers, refugees and populations at risk in developing countries . The beneficial epidemic effect of the lockdowns, obtained at enormous economic costs, would be canceled out if a second wave epidemic should start from these settings with relatively unrestrained viral transmission. At present it is not clear which institution, if not the United Nations' suborganizations, will be able to implement such measures. When the leading nation of the western hemisphere leaves now the WHO, this is a disastrous signal for global public health at this crucial moment of the COVID-19 pandemic.

2020) Visualizing Speech-Generated Oral Fluid Droplets with Laser Light Scattering

100'000 and counting. The Economist

Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility

Airborne or Droplet Precautions for Health Workers Treating COVID-19?

Utility of hyposmia and hypogeusia for the diagnosis of COVID-19

Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study

Investigation of a COVID-19 outbreak in Germany resulting from a single travel-associated primary case: a case series

A Sneeze

England and Wales see 20 000 excess deaths in care homes

Wearing Face Masks in the Community During the COVID-19 Pandemic: Altruism and Solidarity

Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study

Impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an observational study

2020) Pandemics and the great evolutionary mismatch

Rapid implementation of mobile technology for real-time epidemiology of COVID-19

Assessment of Deaths From COVID-19 and From Seasonal Influenza

Coast-to-coast spread of SARS-CoV-2 during the early epidemic in the United States

Asymptomatic Transmission, the Achilles' Heel of Current Strategies to Control Covid-19

Face Masks for the Public During the covid-19 Crisis

Spread of SARS-CoV-2 in the Icelandic Population

Aerosol and Surface Distribution of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospital Wards

Temporal dynamics in viral shedding and transmissibility of COVID-19

Estimates of global seasonal influenza-associated respiratory mortality: a modelling study

Where are the ECDC and the EU-wide responses in the COVID-19 pandemic?

Collateral Effect of Covid-19 on Stroke Evaluation in the United States

Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures

Projecting the Transmission Dynamics of SARS-CoV-2 Through the Postpandemic Period

Effect of nonpharmaceutical interventions to contain COVID-19 in China

Delayed access or provision of care in Italy resulting from fear of COVID-19

COVID-19: a need for real-time monitoring of weekly excess deaths

First-wave COVID-19 transmissibility and severity in China outside Hubei after control measures, and second-wave scenario planning: a modelling impact assessment

Is the Coronavirus Airborne? Experts Can't Agree

The characteristics of household transmission of COVID-19

Epidemiological and clinical characteristics of COVID-19 in adolescents and young adults

An internet-delivered handwashing intervention to modify influenza-like illness and respiratory infection transmission (PRIMIT): a primary care randomised trial

Reducing risks from coronavirus transmission in the home-the role of viral load

Genomic epidemiology of SARS-CoV-2 in Guangdong Province

SARS-CoV-2 Infection in Children

Effective containment explains subexponential growth in recent confirmed COVID-19 cases in China

Antibody Tests Suggest That Coronavirus Infections Vastly Exceed Official Counts

Epidemiology of Covid-19 in a Long-Term Care Facility

Lost in transition

COVID-19 deaths in Lombardy, Italy: data in context

Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) From a Symptomatic Patient

Children with Covid-19 in Pediatric Emergency Departments in Italy

Covid-19 -The Law and Limits of Quarantine

Closing borders is ridiculous': the epidemiologist behind Sweden's controversial coronavirus strategy

Herd immunity: Understanding COVID-19

Failing the Test -The Tragic Data Gap Undermining the U.S. Pandemic Response

Seroprevalence of SARS-CoV-2-Specific Antibodies Among Adults

Coughing and Aerosols

Reviving the US CDC

COVID-19: PCR screening of asymptomatic healthcare workers at London hospital

Effect of changing case definitions for COVID-19 on the epidemic curve and transmission parameters in mainland China: a modelling study

Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study

Virological Assessment of Hospitalized Patients With COVID-2019

Connecting clusters of COVID-19: an epidemiological and serological investigation

Detection of Covid-19 in Children in Early

Changes in Contact Patterns Shape the Dynamics of the COVID-19 Outbreak in China

What is required to prevent a second major outbreak of SARS-CoV-2 upon lifting the quarantine of Wuhan city, China. Preprint to The Lancet

Acknowledgements I thank Jacqueline Steinhauser and Sophie Zuber for critical reading of the manuscript.

The author consults Nestlé, his former employer, on the scientific aspects of the COVID-19 epidemic, but he does not consider this as a conflict of interest.