July 5, 2021
On December 30, 2019, a cluster of pneumonia cases was reported in Wuhan, a city of 11 million in the Chinese province of Hubei (1). The cause was later found to be a novel coronavirus, subsequently named SARS-CoV-2. Its genome was found to be most closely related to a coronavirus isolated from horseshoe bats that are found about 1,000 miles away in caves in the Chinese province of Yunnan.
Similar to the events of the 2002–2003 SARS epidemic, early reports suggested that SARS-CoV-2 had jumped from animals to humans at a live animal food market. In the 2019 outbreak, the suspected source was Wuhan's Huanan Seafood Wholesale Market, where many different species of live animals were clustered in cages, offering opportunities for viral transmission. As a result, the Wuhan market was closed on January 1, 2020; however, evidence now suggests this market was not the source of the outbreak. No pangolins or bats, initially thought to be possible spillover hosts for the novel coronavirus, had been traded at the market. Only one of the first five human cases with confirmed SARS-CoV-2 infection in Wuhan had any link to the Wuhan market (2) and, although environmental samples from the site in the market where live wildlife was sold were positive for SARS-CoV-2, tissue samples from the market's animals were reportedly negative for the virus (3). How this virus made the jump from Yunnan bats to human beings in Wuhan remains unknown.
Wuhan, however, is home to the Wuhan Institute of Virology (WIV), a research facility, located eight miles from the Huanan Seafood Wholesale Market. WIV has specialized laboratories (biosafety level 4, or BSL-4) for work with highly contagious and virulent viral pathogens and is well known for its work with bat coronaviruses. A US intelligence report found that in November 2019, several researchers at WIV fell ill and had to be hospitalized, raising the possibility that SARS-CoV-2 escaped from WIV, possibly via an infected staffer or contaminated object, as a result of a laboratory accident. Lab accidents have happened in the past: For example, in 2015, the US military accidentally shipped live anthrax samples instead of dead spores to up to nine labs across the country and a military base in South Korea. In four instances between 2003 and 2004, the SARS virus was accidentally released at laboratories in Singapore, Taiwan, and Beijing. But at the present time, there is no direct evidence to support the idea of a “lab-leak” at WIV. Wuhan is also home to the Wuhan Center for Disease Control and Prevention, located barely 300 yards from the Huanan market, which studies viruses isolated from bats.
On January 5, 2020, Professor Zhang Yongzhen, at the Shanghai Public Health Clinical Center & School of Public Health, sequenced the novel coronavirus’ genome and uploaded its genetic sequence to the U.S. National Center for Biotechnology Information (NCBI). A week later, he also uploaded the genetic sequence to an open-access database for global use (4).
On January 1, 2020, there were 41 cases in Wuhan. The cumulative case count in Wuhan then doubled every 2.3 to 3.3 days (5). On January 18, 2020, when the cumulative case count had risen to about 4,000 (5), more than 10,000 families in Wuhan attended an annual banquet to celebrate the Lunar New Year. Days later, on January 23, 2 days before Lunar New Year, when many people would have traveled to their hometowns for family reunions, Chinese authorities responded to increasing case counts by locking down about 57 million people living in Hubei Province.
The borders of Wuhan were blocked — allowing no one in or out. People were required to remain in their apartments, increasing the physical distance between people outside of households. Schools and universities closed. All types of recreational venues and most public places closed. Only essential businesses were allowed to remain open. However, an estimated five million people had left Wuhan before the lockdown began, and consequently, the number of cases surged in the surrounding Chinese provinces. By early February 2020, the virus had spread to all provinces of Mainland China (37,000 cases), and patients with a history of travel from Wuhan also began appearing outside China, in places such as Hong Kong and Singapore and the West Coast of the US.
Despite lockdowns in Hubei, by early February, the confirmed case count in Hubei was about 25,000, and a month later, it was 64,000. After 9 weeks of sustained transmission, Hubei Province reported 64,084 confirmed cases with 2,346 deaths. The actual number of cases was probably much higher as only the most severe cases were likely included in reports due to shortages of testing kits. The presence of many undiagnosed mild infections probably limited efforts to control further spread of this infection.
R Naught (R0), or the basic reproductive number, is the average number of cases of an emerging contagious disease directly generated by one case in a population where all individuals are susceptible to the infection. The larger the value of R0, the harder it is to control an epidemic. In Wuhan, the rapidity of spread was high with a reported R0 of 5.7 (range, 3.8 to 8.9), when compared to the 2003 SARS outbreak with an R0 of 2 to 3, suggesting SARS-CoV-2 is much more transmissible than SARS-CoV (5). To explain its greater transmissibility, SARS-CoV-2 is most contagious in the several days before and after the onset of symptoms (unlike SARS-CoV, which is most contagious only after symptoms begin). In addition, up to about 50% of transmissible infections are asymptomatic (or pre-symptomatic), permitting unwitting spread of the infection by asymptomatic individuals. At least 50% of new SARS-CoV-2 infections are estimated to have originated from exposure to individuals with infection but without symptoms at the time of transmission (6). SARS-CoV-2 also has a much higher affinity for the angiotensin-converting enzyme 2 (ACE2) host cell surface receptor on the nasal epithelium than the 2003 SARS virus (7), perhaps providing a molecular basis for the greater contagiousness of SARS-CoV-2.
By early February 2020, the Hubei lockdown began to show an effect; the rate of increase in the daily new case counts first began to slow, and the number of new cases each day began falling in mid-February. On March 8, for the first time since mid-January 2020, the number of newly reported cases in a 24-hour period was less than 50. A week later, there were no new locally acquired cases in Hubei province. In mid-March, the lockdown in Hubei was gradually lifted, and new case counts have remained low. China, the world’s most populous country and the original epicenter of the COVID-19 outbreak, was able to reduce transmission to a manageable level. Currently, most new infections in China are imported from outside the country, and community spread is being limited by isolating cases, tracing contacts, and quarantining contacts.
On March 11, 2020, when community spread was occurring in multiple locations throughout the world and 36 % of the total number of COVID-19 cases were being reported outside Mainland China, the World Health Organization (WHO) declared COVID-19 was pandemic. By then the outbreak in China had subsided and Western Europe, mainly Italy, Spain, Germany, France, and the UK, had become the new hotspots. The rapid rise in the number of new cases each day in these European countries prompted lockdowns, and within the next 14 days (one incubation period for COVID-19), the daily new case counts, after peaking, began dropping. As in Hubei, the impact of lockdowns was seen only when at least one incubation period had passed, allowing for manifestation of symptoms in newly infected individuals who were still in their incubation period at the start of the lockdown.
The next hotspot was in mid-March 2020, in the northeastern region of the US. With rapidly rising daily case counts, New York, New Jersey, Connecticut, and Massachusetts imposed statewide stay-at-home orders and closure of all non-essential businesses on or about March 22, 2020. The daily new case counts continued to increase, peaking in the first week of April 2020, and then falling during the next 14 days, to reach stable lower levels of fewer than 1,000 newly infected cases daily in mid-June 2020, a pattern similar to the response to lockdowns in China and Europe. Nevertheless, if New York, the state with most confirmed cases at the time, were considered a country, the state’s total case count of over 430,000 cases at the time would have been the 5th largest, after the US as a whole (3.6 million), Brazil (almost 2 million), India (almost 1 million), and Russia (almost 750,000). More than half of the state's cases were in New York City, where nearly half the state's population lives.
COVID-19 has since spread throughout the U.S. The number of new cases in the US rose each day to reach an initial peak of about 35,000 on April 9, 2020, and then gradually fell, to be followed by three additional peaks, each peak building off a valley that was higher than the previous one. The three peaks each followed massive loosening of social restrictions: the second peak of 75,000 new cases on July 16 followed the Memorial Day (May 25, 2020) and the July 4th holidays; the large third peak of 300,000 new cases on January 8, 2021, followed Thanksgiving (November 26, 2020) and the Christmas/New Years’ holidays. The fourth peak of about 75,000 new cases on April 14, 2021, followed Spring Break in mid-March, 2021 (8). Thereafter, the number of new cases each day steadily fell to a low of about 4,000 on June 20, 2021, as increasing numbers of the U.S. adult population were vaccinated against COVID-19. Troubling though, the rate of new cases slowed its decline in June 2021, and lately has begun to rise again (9), as more transmissible SARS-CoV-2 variants, such as the delta variant, are replacing less transmissible variants (10). In the US, the total number of confirmed COVID-19 cases since the beginning of the pandemic is now over 33 million, with over 600,000 deaths.
Almost 60% of all vaccine-eligible Americans — those 12 years of age and older, are currently fully vaccinated (11). At present, in the US, most hospitalizations and deaths due to COVID-19 are occurring in people who are not vaccinated: "Breakthrough" infections in fully vaccinated Americans account for fewer than 1,200 of more than 853,000 COVID-19 hospitalizations (0.14%), and for about 150 of the more than 18,000 COVID-19 deaths (0.8%---12). As an increasing proportion of the population is vaccinated, transmission will likely be lessened and the severity of illness, in terms of hospitalizations and deaths caused by SARS-CoV-2, will fall further. Nevertheless, more transmissible variants may likely emerge, especially among people who remain unvaccinated, have received only one dose of a 2-dose vaccine, or whose vaccine-induced immunity has waned. Partial immunity likely will create selective pressure for emergence of variants that more easily escape immune control. Booster vaccinations will likely be needed to maintain effective immunity in vaccinated people with waning immunity (13).
Globally, COVID-19 has affected 220 countries and territories, with an epidemic daily incidence curve similar to that of the US, with 4 peaks on April 10, 2020, July 31, 2020, January 8, 2021, and April 23, 2021, each higher than the preceding peak (14). As of July 5, 2021, there are a total of almost 184 million cases and 4 million deaths worldwide. The reported case counts are underestimates because many acute infections are mild or asymptomatic and not diagnosed and reported. Seroprevalence surveys in the US and Europe have suggested that the number of SARS-CoV-2 infections exceeds the number of reported cases by approximately 10-fold or more (15).
Some countries, such as China, Singapore, Australia, and New Zealand, have aimed for zero COVID-19 cases by strict containment strategies. In contrast to the US, with a total of over 33 million cases (10,151 cases/100,000 population) since the start of the pandemic, China has recorded 105,000 cases (8 cases/100,000 population); Singapore 62,617 cases (1,098 cases/100,000 population); Australia just over 30,000 cases (121 cases/100,000 population); and New Zealand 2,759 cases (56 cases/100,000—16). These countries with relatively low incidence have effectively closed their borders to the outside world to prevent introduction of SARS-CoV-2 into their communities, banning non-citizens from nonessential entry, mandating travelers stay at designated quarantine hotels that are monitored by police, and testing everyone allowed to enter. Exact details of government-imposed quarantines, such as surveillance levels, costs, and lengths of stay, vary from country to country. Nevertheless, these countries still face repeated introductions from endemic regions outside their borders, followed by intense efforts to prevent community spread by periodic local lockdowns, testing on a massive scale, isolating cases, and promptly tracing and quarantining contacts; therefore, containment strategies have been ongoing. How long these countries that have opted for “zero-tolerance” of SARS-CoV-2 transmission can tolerate closed borders has become a matter of debate (17).
Singapore has recently changed course; they have chosen to avoid serious illness and hospitalization from COVID-19 by mass vaccination, while accepting a certain endemic level of COVID-19 in the country – an approach many Western countries are now adopting; 38% of Singaporeans are now fully vaccinated (18). In Australia and New Zealand with low levels of COVID-19 transmission, there is little incentive to vaccinate; currently, only 7.3% of Australians and 9.0% of New Zealanders are fully vaccinated (18). China has distributed over 1 billion COVID-19 vaccinations to its citizens and aims to vaccinate 80% of its population by the end of this year, but China, as well as Australia and New Zealand, are reported to be unlikely to open their borders and will maintain COVID-zero strategies (18, 19).
Over the past six months, hundreds of millions of people have been vaccinated worldwide, but the distribution of vaccines has been uneven, leaving low income countries struggling to vaccinate their populations (20). COVID-19 vaccines currently authorized in the US prevent symptomatic infection, including severe disease, hospitalization, and death, as well as reduce transmission of SARS-CoV-2 to others. Failure to fully vaccinate much of the developing world could allow uncontrolled transmission to persist, giving the virus the chance to mutate and possibly spill over into developed countries, where the variants have caused severe disease, hospitalizations and death mainly in the unvaccinated portions of the population. COVID-19 in fully immunized people, known as a breakthrough infection, due to these variants has usually been less severe than in the unvaccinated. However, a variant may eventually emerge that causes deadly infection even in the fully vaccinated. It is a race to stay ahead of virus evolution by immunizing the world’s population before a deadly variant emerges that escapes immune control. It is hoped that at that point both a vaccine that can effectively target this variant and highly effective antiviral drugs are available. The utility of periodic additional doses of one of the existing vaccines to boost immunity or a revised vaccine that targets variants, as is done for influenza, is unknown at present.
Transmission of SARS-CoV-2
SARS-CoV2 is thought to spread mainly person-to-person by:
Airborne Transmission (Large Droplet and Aerosol): People expel respiratory fluid particles of varying sizes carrying virus for a variable distance, when coughing, sneezing, exercising, talking, singing, sneezing, and even quietly breathing. The larger heavier particles (> 5 microns) rapidly settle out within 6 feet, but smaller lighter particles (< 5 microns) in the form of aerosols can remain suspended in air for minutes to hours and be carried by air currents a considerable distance from the infectious source. SARS-CoV-2 virus has been found to remain viable in aerosols for at least 3 hours under laboratory conditions (23). Increasing evidence suggests that transmission of SARS-CoV-2 commonly occurs via aerosolized droplets especially in superspreading events, when a single index case is able to infect a large number of secondary cases more than six feet from the index case.
Studies using polymerase chain reaction (PCR) have detected viral RNA in respiratory secretions for up to weeks after symptom onset, but PCR does not necessarily detect live, infectious virus. When studying contacts of index cases, the period of greatest transmission is within 5 days of symptom onset; transmission also occurs during the pre-symptomatic period of index cases (24). This observed pattern of secondary cases is consistent with the number of SARS-CoV-2 viral particles in upper respiratory specimens as measured by PCR, being highest at the time of symptom onset (25) and by viral culture, live virus being isolated only during the week after symptom onset (26–29).
Epidemiologic studies of clusters of cases suggest that only a minority of infected people account for most secondary cases, that is, about 20% of infected people are responsible overall for 80% of the infections (30, 31). A large cluster of cases traced to a single individual index case is called a superspreading event. Superspreaders played an extraordinary role in driving the 2003 SARS outbreak and are similarly playing a significant role in the current COVID-19 outbreak. Multiple factors can contribute to superspreading, including behavior of the index case that exposes a large number individuals, prolonged duration of exposure, crowding in an enclosed space, poor ventilation, and the transmissibility, virulence and the amount of the virus in the respiratory secretions of the index case.
One example of a superspreading event was a 2.5-hour choir practice in a church in Washington State, USA in March 2020. The rehearsal was attended by 61 people, including a symptomatic index patient, after which 33 confirmed and 20 probable secondary cases were identified; three patients were hospitalized and two died (32). This outbreak was most likely caused by an aerosol, as singing itself is known to generate aerosols, and most of the secondary cases were likely seated more than 6 feet from the index case, beyond the range of large respiratory droplets.
Another example of a superspreading event was a pharmaceutical company conference in Boston in February 2020. The conference was attended by a large number of international participants and resulted in more than 100 cases among the attendees. Once the conference ended, attendees headed to their homes around the world. Because SARS-CoV-2 viruses circulating at the conference had distinct genomic signatures, additional cases could be traced beyond the superspreading event itself. Subsequent spread made a large contribution to local outbreaks in the Boston area, throughout the US, and internationally, eventually causing hundreds of thousands of COVID-19 cases (33).
An important concept in airborne transmission, especially in confined indoor spaces with poor ventilation, is “sharing air,” where people are inhaling the air exhaled by an index case. The carbon dioxide (CO2) level in air in occupied indoor space is an important indicator of the adequacy of indoor ventilation. The carbon dioxide concentration in exhaled air is about 38,000 ppm (parts per million), which quickly falls to levels approaching outdoor CO2 levels as the surrounding air dilutes it, if the ventilation is good. Outdoor CO2 levels are currently about 420 ppm (34).
The risk of transmission in indoor settings appears to be substantially greater than outdoors, where virus-laden respiratory particles can disperse more easily, although, even outdoors, close contact (within 6 feet) with an infected individual likely remains a risk. In poorly ventilated indoor spaces filled with people, carbon dioxide levels build up, reaching concentrations far above the baseline level of outside air. The higher the carbon dioxide concentration in a room occupied by a contagious person, the more likely the inhaled air will contain viral particles. When the indoor concentration of carbon dioxide reaches 800 ppm, then 1% of the air inhaled has been calculated to come from air exhaled by others (35).
The American Society of Heating, Refrigeration, and Air Conditioning Engineers (ASHRAE) recommends that indoor carbon dioxide levels not exceed the outdoor concentration (about 420 ppm) by more than about 600 ppm, as a measure of the adequacy of indoor ventilation (36). California designated 800 ppm as the maximum carbon dioxide level in occupied commercial indoor space (37). In Washington State, if indoor carbon dioxide levels in a restaurant exceed 450 ppm for 15 minutes, diners must be relocated to an open‐air seating option (38).
Fomites: SARS-CoV-2 can contaminate and survive on environmental surfaces for a variable period of time, depending surface characteristics. Under experimental conditions, SARS-CoV-2 remains viable for up to 72 hours on plastic or steel, up to 4 hours on copper, and up to 24 hours on cardboard (23). The transfer of virus from contaminated environmental surfaces (called fomites) occurs when hands that have been soiled by touching virus-contaminated surfaces then touch mucous membranes on the face (nose, mouth, eyes). Frequently touched surfaces in public places, including elevator buttons, door handles, and TV remote controls, are particularly hazardous. Both cleaning (use of soap or detergent) and disinfection (use of a product or process designed to inactivate SARS-CoV-2) can reduce the risk of fomite transmission.
The risk of fomite transmission is considered to be low compared with risks from large droplet transmission or aerosol-borne transmission (39). The risk is dependent on the prevalence of COVID-19 in the community, the time between surface contamination and when the surface is touched, the amount of virus infected people expel (which can be substantially reduced by wearing masks), and the dose of virus needed to cause infection through the mucous membrane route. The CDC recommends that when there has been a suspected or confirmed case of COVID-19 indoors within the prior 24 hours and the presence of infectious virus on surfaces is more likely, high-touch surfaces should be disinfected (39 [reference 26]).
Special Settings: Certain types of settings have been noted where SARS-CoV-2 is most likely to be transmitted and give rise to clusters of COVID-19 cases (40). These settings are predominately indoors, where individuals reside, work, or otherwise congregate in close quarters for prolonged periods of time (41) and include households (42), long-term care facilities (43), cruise ships (44), homeless shelters (45), prisons (46), college dormitories (47), worker dormitories (48), religious gatherings (49), bars (50.), and food processing facilities (51).
Transmission of SARS-CoV-2 within households is common and has been reported to occur rapidly (eg, within 5 days) after onset of the index patient’s illness and occur whether the index patient was an adult or a child (42). Prompt isolation of persons with COVID-19, even within the household, self-quarantine of close household contacts of the index patient, and masking of all household members, including the index case, within shared spaces in the household, can reduce further transmission (52, 53). Isolation is recommended to start on suspicion of the diagnosis while awaiting confirmatory test results, because delaying isolation until confirmation of infection could miss an opportunity to reduce transmission to others. (42).
Cruise ships, prisons, long-term care facilities, and to some extent, college and worker dormitories share common characteristics that make them vulnerable to outbreaks of contagious diseases: they are densely populated congregate settings. They may have a central kitchen that serves meals to large gatherings; group activities occur in enclosed environments; and a staff member may have extensive contact with the residents in the dining halls and recreational rooms (54). Both cruise ships and long-term care facilities also have high proportions of older individuals who tend to be more vulnerable to COVID-19, and both are known to have had problems with infection control (55–57 ). Even in these close quarters, for example, among the passengers on cruise ships, aerosols have been estimated to be more of a contributor to COVID-19 transmission, than large respiratory droplets or fomites (58).
Transmission has also occurred in nightclubs. For example, more than 100 cases were linked to nightlife venues in the Seoul, South Korea, after lockdown measures were eased. Bars and nightclubs where the combination of alcohol intoxication, crowding, people not wearing face masks trying to talk above each other and over loud music are typical high-risk settings. Shouting propels viral-loaded respiratory droplets further. Air conditioners may contribute to spread, potentially blowing smaller respiratory droplets along the path of the air conditioner’s airflow. An additional factor is likely the use of public restrooms, with high-touch surfaces contaminated by unwashed hands, coupled with aerosols generated by flushing lid-free toilets with SARS-CoV-2-contaminated feces.
On airplanes, the risk of secondary infection is highest for individuals in seats adjacent to an index patient, and higher for those seated in the same row than for those in front or behind. The risk also increases the longer the duration of travel. For example, on a 10-hour flight from London to Hanoi, of the 16 persons in whom SARS-CoV-2 infection was detected, 12 (57%) of the 21 passengers who shared business class with a symptomatic index patient were infected. Almost all of the infected individuals (11 of 12) had been seated within 6 feet of the index case. The other infected travelers had been seated in economy class and may have had contact with the index patient on arrival at immigration or at baggage claim. (59). The authors noted that thermal temperature screening and self-reporting of symptoms at the airport did not stop the infected person from boarding. At that time, the use of face masks was not mandatory on airplanes or at airports. However, in another study, transmission occurred on an international flight despite the reported in-flight use of masks (60). The US CDC requires all passengers and staff to wear masks on public conveyances (eg, airplanes, ships, ferries, trains, subways, buses, taxis, ride-shares) traveling into, within, or out of the United States, regardless of their vaccination status, and also recommends staying 6 feet from others at the airport (61). On the airplane, based on laboratory modeling of exposure to SARS-CoV-2, leaving a vacant middle seat has been reported to reduce risk for exposure to SARS-CoV-2 from nearby passengers (62).
Transmission from animal contact: Although SARS-CoV-2 infection is thought to have been transmitted initially to humans from an animal host, specifically a horseshoe bat from Yunnan, there have been no reports of domesticated or wild animals, other than mink, transmitting SARS-CoV-2 infection to humans. SARS-CoV-2 infection in farmed mink has been reported in Denmark, the Netherlands, and the United States, and transmission from infected mink to Danish mink farm workers was found to be caused by a unique SARS-CoV-2 variant (called Cluster 5—63). These reports prompted culling all farmed mink in both Denmark and the Netherlands. Because farmed mink can transmit SARS-CoV-2 to co-housed mink, spread of infection from escaped infected farmed mink to wild mink populations is possible, establishing new reservoirs in susceptible wildlife that possibly could reintroduce infection into human populations (64).
Mink are mustelids, a family of mammals that also include ferrets, weasels, badgers, otters, martens, sables, and wolverines; all mustelids are susceptible to SARS-CoV-2 infection. In fact, ferrets, which are highly susceptible to SARS-CoV-2 infection, are being used in pre-clinical trials for drug and vaccine development. SARS-CoV-2 vaccines for use in farmed mink are now being developed.
Other animals susceptible to SARS-CoV-2 infection include domestic dogs, felines (domestic cats and tigers, lions, cougar, and snow leopard in zoos), and non-human primates, including all apes (chimpanzees, bonobos, gorillas and orangutans) and Old World monkeys. Among rodent species, the Syrian hamster and the North American deer mouse are reported to be highly susceptible and able to transmit SARS-CoV-2 to co-housed contact animals and therefore could develop effective infection chains in nature (65). Another rodent, the bank vole, is also susceptible to SARS-CoV-2 infection, but it does not transmit SARS-CoV-2 to other voles, making it unlikely to maintain sustainable infection in nature (65). Unlike older versions of the SARS-CoV-2 virus, the beta and gamma variants have been reported to infect common laboratory mice (66). The original strain of SARS-CoV-2 only could infect “humanized mice”, a special strain of mice that has been genetically modified to carry human ACE2 receptors on the surface of their respiratory tract cells. This abrogation of the species barrier by the beta and gamma variants raises the possibility of secondary wild rodent reservoirs for these variants.
Although there is no evidence that animals play a significant role in spreading SARS-CoV-2 at present, the establishment of reservoirs of SARS-CoV-2 in free-living wildlife, such as mustelids, rodents, felines, or non-human primates, would create significant challenges for control of infection in humans (67).
The US CDC recommends that pets be kept away from other animals or people outside of the household and that people with confirmed or suspected COVID-19 should avoid close contact with household pets for the duration of their self-isolation period (68).
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