COVID Reference

Six weeks after the third edition, the world has changed again. The pandemic is raging in South America, particularly in Brazil, Ecuador and Peru. SARS-CoV-2 is under control in China, but in Iran it is not. And in Europe, where most countries have weathered the first wave and open borders to save a compromised tourist season, is now wondering if and for how long this biological drôle de guerre could last.

Science has moved ahead, too. We have seen a more complex picture of COVID-19 and new clinical syndromes; the first data from vaccine trials; first results from randomized controlled drug studies; encouraging publications on monoclonal neutralizing antibodies and serological evidence about the number of people who have come into contact with SARS-CoV-2. Unfortunately, we have also seen the first science scandal with fake data published in highly ranked journals. And we face new challenges like long-term effects of COVID-19 and a Kawasaki-like inflammatory multisystem syndrome in children.

For quite some time, prevention will continue to be the primary pillar of pandemic control. In future waves of the SARS-CoV-2 pandemic, we will focus on the conditions under which SARSCoV-2 is best transmitted: crowded, closed (and noisy) places and spaces. Although hospitals are not noisy, they are crowded and closed, and the battle against the new coronavirus will be decided at the very center of our healthcare system. Over the next months and maybe years, one of all of our top priorities will be to give all healthcare workers and patients perfect personal protective equipment.


Bernd Sebastian Kamps Stefano Lazzari

In December 2019, several patients from Wuhan, People’s Republic of China, developed pneumonia and respiratory failure reminiscent of the SARS epidemic in 2003. In early January 2020, a new virus was isolated from bronchoalveolar lavage fluid samples and found to be a betacoronavirus (Zhou 2020). Between then and the time of this writing (7 June), the virus, later denominated SARS-CoV-2, has spread to every corner of the world. Millions have been diagnosed with SARS-CoV-2 infection and hundreds of thousands of people have died of COVID-19, the disease caused by SARS-CoV-2. SARS-CoV-2 has the potential to cause a long- lasting pandemic with high fatality rates.

The transmission of SARS-CoV-2 is discussed in a separate chapter (page 71) which highlights that SARS-CoV-2 is easily transmissible both by symptomatic and asymptomatic individuals; it thrives in closed and densely inhabited environments; and is amplified by so-called ‘superspreader’ events. There is evidence that in China, human-to-human transmission has occurred among close contacts since the middle of December 2019 (Li Q 2020). In Italy and France, SARS-CoV-2 was circulating as early as January among asymptomatic or paucisymptomatic people (Cereda 2020, Gámbaro 2020). In the Greater Paris Region, after retesting samples from 24 patients treated in December and January, one sample collected on December 27 was retrospectively found to be positive for COVID (France 24, 5 May 2020). The samples had initially been collected to detect flu using PCR tests.

The mean incubation period of SARS-CoV-2 infection is around 5 days (Li 2020, Lauer 2020, Nie X 2020). The serial interval – de- fined as the duration of time between a primary case-patient having symptom onset and a secondary case-patient having symptom onset – has been estimated to be between 5 and 7.5 days (Cereda 2020). SARS-CoV-2 is highly contagious, with an estimated basic reproduction number R0 of around 2.5-3.0 (Chan 2020, Tang B 2020, Zhao 2020). [R0 indicates the average number of infections one case can generate over the course of the infectious period in a naïve, uninfected population.]

Hospitals and other health care centers

There is no doubt that transmission in hospitals and other health care centers (including doctors offices) played a prominent role in the origin and spread of local epidemics, especially in the be- ginning when suspicion of the disease was low. This is reminiscent of the largest MERS outbreak outside of the Arabian peninsula which occurred in the Republic of Korea in 2015. Of the 186 cases, 184 were infected nosocomially (Korea Centers for Disease Control and Prevention 2015).

Hospitals are a favorable environment for the propagation of SARS-CoV-2 (Wison 2020). In some instances, hospitals could have been even the main COVID-19 hub, as they were rapidly populated by infected patients, facilitating transmission to health workers and uninfected patients (Nacoti 2020). Within the first 6 weeks of the epidemic in China, 1,716 cases among health care workers were confirmed by nucleic acid testing, and at least 5 died (0.3%) (Wu 2020).

One hospital study reports that the virus was widely present in the air and on object surfaces in both the intensive care units and general wards, implying a potentially high infection risk for medical staff. Contamination was greater in ICUs. Virus was found on floors, computer mice, trash cans, sickbed handrails, and was detected in the air up to approximately 4 m from patients (Guo 2020). The virus was also isolated from toilet bowl and sink samples, suggesting that viral shedding in stool could be a potential route of transmission (Young 2020, Tang 2020). However, most of these studies have evaluated only viral RNA. It remains to be seen whether this translates into infectious virus.

Although nosocomial spread of the virus is well documented, appropriate hospital infection control measures can prevent nosocomial transmission of SARS-CoV-2 (Chen 2020). This was nicely demonstrated by the case of a person in her 60s who travelled to Wuhan on Dec 25, 2019, returned to Illinois on Jan 13, 2020, and transmitted SARS-CoV-2 to her husband. Although both were hospitalized in the same facility and shared hundreds (n=348) of contacts with HCWs, nobody else became infected (Ghinai 2020).

However, working in a high-risk department, longer duty hours, and suboptimal hand hygiene after coming into contact with patients, are all associated with an increased risk of infection in health care workers (Ran 2020). At one time, during the early epidemic in March 2020, around half of 200 cases in Sardinia were among hospital and other health care workers. On 14 April, the US CDC reported that 9,282 Health Care Personnel has been infected with SARS-COV-2 in the USA.

The risk factors for SARS-CoV-2 infection in health care workers has recently been summarized in a review. There is evidence that more consistent and full use of recommended PPE measures was associated with decreased risk for infection, suggesting a dose–response relationship. Association was most consistent for masks but was also observed for gloves, gowns, and eye protection, as well as hand hygiene. Some evidence was found that N95 respirators might be associated with higher reduction of risk for infection than surgical masks. Evidence also indicated an association between certain exposures (such as involvement in intubations, direct contact with infected patients, or contact with bodily fluids) (Chou 2020).

SARS-CoV-2 outbreaks can occur everywhere, not only in admission, infectious disease and intensive care units. In a pediatric dialysis unit in Münster (Germany), a healthcare worker infected 7 colleagues, three young patients and one accompanying person (Schwierzeck 2020). A Chinese study of 9,684 healthcare workers (HCW) in Tongji Hospital confirmed a higher rate of infection in non-first-line HCW (93/6.574, 1.4%) when compared to those who worked in fever clinics or wards (17/3110, 0.5%) (Lai X 2020). Those who work in clinical departments other than fever clinics and wards may have neglected to adopt adequate protective measures.

In a well-documented report about nosocomial transmission recently published, a man sought help for coronavirus symptoms on March 9, spending only a few hours at the emergency department of a hospital in Durban, South Africa. He was kept separate in a triage area, but that room was reached through the main resuscitation bay, where a stroke patient occupied a bed. Both patients were seen by the same doctor. After being infect- ed, the stroke patient caused a chain of transmission with 39 patients and 80 staff in 16 different departments being infected, and 15 patients dying. The study found that patients infected few other patients directly. Instead staff members spread the disease from patient to patient and from department to department, perhaps sometimes without becoming infected themselves (Nordling 2020). Strictly enforcing infection control measures and screening hospital staff will be important measures in future waves of COVID-19.

Long-term care facilities

Long-term care facilities are high-risk settings for infectious respiratory diseases. In a skilled nursing facility in King County, Washington, US, 167 cases of COVID-19 were diagnosed within less than three weeks from the identification of the first case: 101 residents, 50 health care personnel and 16 visitors (McMichael 2020) (Table 1).

Among residents (median age: 83 years), the case fatality rate was 33.7%. Chronic underling conditions included hypertension, cardiac disease, renal disease, diabetes mellitus, obesity, and pulmonary disease. The study demonstrates that once introduced in a long-term care facility, often by a care worker or a visitor, SARS-CoV-2 has the potential to spread rapidly and widely, with devastating consequences.

A national survey covering 96% of all long-term care facilities in Italy found that in Lombardy, the epicenter of the epidemic, 53.4% of the 3,045 residents who died between 1 February and 14 April were either diagnosed with COVID-19 or presented flu-like symptoms, a death rate among residents of 6.7%. Among the 661 residents who were hospitalized during the same period, 199 (30%) were found positive by a PCR test. According to WHO estimates, in countries in the European Region up to half of those who have died from COVID-19 were residents in long-term care facilities (see the statement to the press by Hans Henri P. Kluge, WHO Regional Director for Europe). Excess mortality data suggests that in several countries many deaths in long-term care facilities might have occurred in patients not tested for COVID- 19, which are often not included in the official national mortality statistics.

SARS-CoV-2 continues to spread in US nursing homes where approximately 1.3 million Americans reside (CDC 200311). In mid- April, more than 1,300 facilities had identified infected patients (Cenziper 2020). As most residents have one or more chronic underling condition such as hypertension, cardiac disease, renal disease, diabetes mellitus, obesity and pulmonary disease, COVID-19 puts them at high risk for premature death.

Cruise ships

Cruise ships carry many people in confined spaces. On 3 February 2020, 10 cases of COVID-19 were reported on the Diamond Princess cruise ship. Within 24 hours, all sick passengers were isolated and removed from the ship and the rest of the passengers quarantined on board. Over time, more than 700 of 3,700 passengers and crew tested positive (around 20%). One study suggested that without any intervention 2,920 individuals out of the 3,700 (79%) would have been infected (Rocklov 2020). The study also showed that an early evacuation of all passengers on 3 February would have been associated with only 76 infected.

For cruise ships, SARS-CoV-2 may spell disaster as carrying village loads of people from one place to another may not be a viable business model until the global availability of a safe and efficient vaccine.

Aircraft carriers and other military vessels

Big navy vessels such as aircraft carriers can become floating petri dishes for emerging viral respiratory diseases. Already in 1996, an outbreak of influenza A (H3N2) occurred aboard a navy ship. At least 42% of the crew became ill within few days, alt- hough 95% had been appropriately vaccinated (Earhart 2001). Since the beginning of the year, several outbreaks of COVID-19 on military ships have been reported, facilitated by the small enclosed areas of work and the lack of private quarters for the crew. The largest outbreaks have been reported on the USS Theodore Roosevelt and the French aircraft carrier Charles de Gaulle. During the Theodore Roosevelt outbreak in late March, around 600 sailors out of a crew of 4,800 were infected with SARS-CoV-2 (see also the March 30 entry of the Timeline); around 60% remained asymptomatic. One active duty sailor died (USNI News). On the French aircraft carrier Charles-de-Gaulle, a massive epidemic was confirmed on 17 April. Among the 1,760 sailors, 1,046 (59%) were positive for SARS-CoV-2, 500 (28%) presented symptoms, 24 (1.3%) sailors were hospitalized, 8 on oxygen therapy and one in intensive care.

Smaller clusters have also been reported on 5 other US military vessels, and in one each from France, Taiwan, and Holland. How- ever, given usual security policies and communication restrictions of national armies and navies, it is possible that other unreported cluster of cases and even deaths might have occurred. For aircraft carriers, the potential for further outbreaks at any time might well interfere with full operability.

Mass gatherings

Several mass gathering events have been associated with explosive outbreaks of COVID-19. As of April 24, 2020, a total of 5,212 coronavirus cases were related to an outbreak at the Shincheonji Church in South Korea, accounting for about 48.7% of all infections in the country.

A football match played in Milan, Italy on 19 February 2020 has been described as “Game zero” or “a biological bomb”. The match was attended by 40,000 fans from Bergamo and 2,500 from Valencia and played just two days before the first positive case of COVID-19 was confirmed in Italy. 35 percent of Valencia’s team members tested positive for the coronavirus a few weeks later, as did several Valencia fans. By mid-March, there were nearly 7,000 people in Bergamo who had tested positive for the corona- virus with more that 1,000 deaths, making Bergamo the most heavily hit province during the COVID-19 outbreak in Italy. Valencia also had 2,600 cases of the infection. The annual gathering of the Christian Open Door Church held between 17 and 24 February in Mulhouse, France, was attended by about 2,500 people and became the first significant cluster in France. After a parishioner and 18 family members tested positive on 1 March, a flurry of reported cases brought the existence of a cluster to light. According to an investigative report by France Info, more than 1,000 infected members from the rally in Mulhouse contributed to the start of the COVID-19 epidemic in France. A large number of diagnosed cases and deaths in France as well as Switzerland, Belgium and Germany were linked to this gathering.

Religious celebrations

One report describes 35 confirmed COVID-19 cases among 92 attendees at church events during March 6–11. The estimated attack rates ranged from 38% to 78% (James 2020). In Frankfurt, Germany, one of the first post-lockdown clusters started during a religious ceremony held on 10 May. As of 26 May, 112 individuals were confirmed to be infected with SARS-CoV-2 (Frankfurter Rundschau). The bottom line: Going to church does not protect from SARS- CoV-2.

Schools and schoolchildren

Schoolchildren usually play a major role in the spread of respiratory viruses, including influenza. However, while the SARS-CoV- 2 virus has been detected in many children, they generally experience milder symptoms than adults, need intensive care less frequently and have a low death rate.

The possible role of children in SARS-COV-2 transmission is still unclear. In a small COVID-19 cluster detected in the French Alps at the end of January, one person returning from China infected eleven other people, including a nine-year-old schoolboy. The researchers closely tracked and tested all contacts (Danis 2020). The boy had gone to school after showing COVID-19 symptoms and was estimated to have had more than sixty high-risk close contacts. No one was found positive to the coronavirus, though many had other respiratory infections. Also, no virus was found in the boy’s two siblings who were on the same Alpine vacation. The researchers concluded that “because children are less likely to become infected and symptoms are milder, they may play a less important role in the spread of the new virus”.

A Norwegian Institute of Public Health review of the role of children in the transmission of SARS-CoV-2 found five documented cases of likely spread of disease from children, but concluded that the evidence is sparse and it is too early to say if children play an important role in the spread of the disease (Fretheim 2020). However, a pre-print study of SARS-CoV-2 viral load by patient age conducted by the Institute of Virology, Charité Universitätsmedizin Berlin, did not find any statistical difference in viral load in different age groups, concluding that children may be as infectious as adults and suggesting to use caution in the re-opening of schools and kindergartens in the present situation (Jones 2020). The debate continues.


According to the WHO, people deprived of their liberty, such as people in prisons and other places of detention, are more vulnerable to the coronavirus disease (COVID-19) outbreak (WHO 200315). People in prison are forced to live in close proximity and thus may act as a source of infection, amplification and spread of infectious diseases within and beyond prisons. The global prison population is estimated at 11 million and prisons are in no way “equipped” to deal with COVID-19 (Burki 2020). The UN High Commissioner for Human Rights, Michelle Bachelet, has encouraged governments to release inmates who are especially vulnerable to COVID-19, such as older people, as well as low-risk offenders, and a number of countries are taking action to try to reduce the prison population.

As of 21 April, SARS-CoV-2 was present in US correctional and detention facilities. Aggregated data on cases from 37 of 54 state and territorial health department jurisdictions revealed 4,893 cases and 88 deaths among incarcerated and detained persons and 2,778 cases and 15 deaths among staff members (Wallace 2020).

Homeless shelters Testing in 1,192 residents and 313 staff members in 19 homeless shelters from 4 US cities (see table), initially triggered by the identification of a COVID-19 cluster, found infection rates of up to 66% (Mosites 2020). In another report from Boston, Massachusetts, 147/408 (36%) homeless shelter residents were positive. Of note, 88% had no fever or other symptoms at the time of diagnosis (Baggett 2020). Industrial meat-packing plants

On 5 May 2020, the German magazine DER SPIEGEL reported that more than 600 employees were infected with SARS-CoV-2 at meat processing plants in Germany. One week later, The Guardian reported that almost half of the current COVID-19 hotspots in the US were linked to meat processing plants where poultry, pigs and cattle are slaughtered and packaged. At the same time, around a hundred people tested positive in two meat processing plants in France (Le Monde). Promiscuity, cold and humid conditions are currently favored as explanations for these unusual outbreaks.

Choirs On 8 March 2020, the Amsterdam Mixed Choir gave a performance of Bach’s St John Passion in the city’s Concertgebouw Auditorium. Days later, the first singers developed symptoms and in the end 102 of 130 choristers were confirmed to have COVID- 19. One 78-year-old choir member died, as did three colleagues; some singers required intensive care (The Guardian, 17 May).

On 9 March, members of the Berlin Cathedral Choir meet for their weekly rehearsal. Three weeks later, 32 out of 74 choir members were positive for SARS-CoV-2 (NDR 2020). All recovered. On 10 March 2020, 61 members of a Skagit County, Washington, choir met for a 2.5-hour practice. A few weeks later, researchers reported that 32 confirmed and 20 probable secondary COVID-19 cases had occurred (attack rate = 53.3% to 86.7%); three patients were hospitalized, and two died. The authors conclude that transmission was likely facilitated by close proximity (within 6 feet) during practice and increased virus diffusion by the act of singing (Hamner 2020).

These data suggest that any noisy, closed and stagnant air environments (e,g, discos, pubs, birthday parties, restaurants, butchering facilities, etc.) where people stand, sit or lie close together and are required to shout for communication are ideal conditions for generating large SARS-CoV-2 outbreaks.

SARS-COV-2 re-activation or re-infection?

In South Korea and elsewhere more than 100 people who had recovered from COVID-19 were retested positive (Ye 2020) and there was concern that patients who recover from COVID-19 may be at risk of reinfection. However, there was no indication that they were contagious. The most likely explanation is that the ‘infection had been reactivated’ in the patients or that the tests picked up non-infective RNA of the virus. Very preliminary data from an animal study (n=2) suggest that that immunity acquired following primary infection may protect upon subsequent expo- sure to the virus. Infection of rhesus macaques with SARS-CoV-2 and re-infection after recovery showed that there was no viral 33 replication in nasopharyngeal or anal swabs, nor any other signs of COVID-19 disease recurrence (Bao 2020).

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