Nature Medicine Paper Points Out A New Coronavirus That Threatens Human Health

- Feb 02, 2020-

In late December 2019, Wuhan, China reported a group of patients with "atypical pneumonia" of unknown etiology. A new type of human coronavirus (now temporarily called "SARS-CoV-2") has been identified as the cause of this disease (now named "COVID-19").


It is increasingly recognized that coronaviruses can cause major emerging viral disease threats. The two most recent examples are severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The two coronaviruses (229E and OC43) circulating in humans come from animals. The SARS-CoV-2 outbreak of coronavirus started in December 2019. The World Health Organization declared the epidemic on January 30, 2020 as a public health emergency of international concern (Public Health Emergency of International Concern). The reported COVID-19 cases and deaths have exceeded the SARS or MERS cases and deaths. In a new study, Leo L. M. Poon and Malik Peiris of the School of Public Health at the Li Ka Shing School of Medicine of the University of Hong Kong in China highlighted some important recent findings related to this global epidemic. The related research results were published in the journal Nature Medicine with the title of "Emergence of a novel human coronavirus threatening human health".


SARS-CoV-2 can be easily cultivated from clinical specimens, and virus isolates are now available in mainland China and elsewhere. SARS-CoV-2 is genetically similar to other coronaviruses in the subgenus Sarbecovirus, which is a beta composed of the SARS-CoV coronavirus that causes SARS and other SARS-CoV-like coronaviruses found in bats Coronavirus clade. Recombination between coronaviruses is common, and SARS-CoV is considered to be a recombinant between bat Sarbecoviruses. Interestingly, the entire genome of SARS-CoV-2 is highly similar to the genome of a bat coronavirus detected in 2013 (> 96% sequence identity), indicating that the direct ancestor of SARS-CoV-2 is already in bats Has spread for at least a few years.


A genome-wide analysis of SARS-CoV-2 indicates that the epidemic is caused by the introduction of a zoonotic disease, and the virus is relatively genetically stable in humans. According to reports, the first human aggregation case was related to contact with a seafood market known for selling wild animals for food. As observed in the SARS epidemic, the zoonotic transmission of SARS-CoV-2 may involve one or more intermediate hosts. However, some of the earliest cases have not been exposed to this seafood market in epidemiology. Therefore, it is unclear whether the initial zoonotic jump was directly transmitted from bats to humans, or whether intermediate mammalian species were involved. It is very important to determine the source of early zoonotic diseases, because unless the initial route of transmission of zoonotic events is determined and interrupted, it is likely that further zoonotic transmission events will occur.


Previous studies on several bat SARS-CoV-like coronaviruses have shown that some of these viruses can be infected with the human receptor ACE-2. It is expected that the spike protein of SARS-CoV-2 is structurally similar to that of SARS-CoV. In fact, it can be bound by a monoclonal antibody specific for SARS-CoV spike protein. Although the key amino acid residues essential for binding to ACE-2 are mutated in the spike protein of SARS-CoV-2, this new coronavirus can use human, pig, bat, and civet ACE-2 in experiments , But cannot use mouse ACE-2 to enter host cells. In theory, the spike protein of SARS-CoV-2 can also interact with ACE-2 of other animals.


In the first 99 clinical reports of patients diagnosed with SARS-CoV-2 infection, the common symptoms were fever and cough (> 80%). Shortness of breath (31%) and muscle pain (11%) were also found in these patients. Unlike patients infected with the human coronavirus that causes the common cold, runny nose and sore throat are rare in hospitalized patients (≤5%), but may be more common in patients with milder conditions. In the hospital-based case series, radiological evidence of bilateral (75%) or unilateral (25%) pneumonia was found, sometimes with multiple mottling and ground-glass turbidity (ground- glass opacities). 17% of patients have acute respiratory distress syndrome, which sometimes leads to multiple organ failure and death. Approximately 75% of patients require supplemental oxygen, while 13% require mechanical ventilation. The ages of these patients range from 21 to 82 years, of which 67% of patients are older than 50 years of age, and 51% of patients have potential comorbidities. Their clinical manifestations and progression are similar to those of MERS or SARS patients.


Recent clustered case data suggest that the overall clinical manifestations of this disease may be more heterogeneous. Upper respiratory tract symptoms such as sore throat and nasal congestion, as well as diarrhea, can occur in milder cases. Radiological evidence of pneumonia can occur even in asymptomatic infections. These clustered cases also indicate that the elderly are related to more serious diseases, and the severity of the young people and children gradually decreases. An increase in the severity of age-related diseases has also been observed in SARS.


Lower respiratory tract samples (such as sputum) seem to have a higher viral load than upper respiratory tract samples (such as throat swabs). Viral RNA has also been detected in blood and stool samples, but people do not know whether these non-respiratory samples are infectious. Considering that the stool samples of SARS patients are infectious under certain circumstances (for example, the Hong Kong Amoy Gardens incident), it is recommended to take measures to prevent stool-to-mouth transmission.


In addition to some early cases of COVID-19, subsequent human infections are also caused by sustainable interpersonal transmission. Using the first 425 confirmed cases in Wuhan, Li et al. Estimated the average incubation period of SARS-CoV-2 infection to be 5.2 days (95% confidence interval (CI), 4.1 to 7.0). About 95% of the cases were 12.5 Symptoms appear within days, so the currently recommended 14 days of medical observation or isolation is reasonable. The number of regenerations (R0, the number of secondary cases expected in fully susceptible populations) and epidemic doubling time are estimated to be 2.2 (95% CI, 1.4-3.9) and 7.4 days (95% CI, 4.2 to 14). Other people's research has also obtained roughly similar values. This is comparable to what was observed during the SARS epidemic. However, the spread of SARS-CoV-2 may occur in patients with mild disease. Whether the spread will occur later in the incubation period is still controversial. This is in sharp contrast to the mode of transmission observed during the SARS epidemic: SARS transmission occurs only 4 to 5 days after the onset of symptoms, and rarely occurs before this. Taken together, these findings suggest that public health interventions that successfully interrupt the spread of SARS-CoV are unlikely to be equally effective in the current COVID-19 epidemic.


Wu et al. Estimated that there were more than 75,000 infected people in Wuhan between December 1, 2019 and January 25, 2020 by using export case data and travel mode data from Wuhan. Based on current trends, and assuming a decline in the spreadability due to intervention, they predict that the outbreak in Wuhan will peak in April 2020. They also predict that the epidemic will continue to grow exponentially outside Wuhan. Their simulations further show that public health interventions can reduce the spread of the disease by 50%, but without reducing population mobility, the exponential growth of the disease can be significantly delayed by at least a few months. Although active disease control measures, such as school suspensions and social isolation, may delay the establishment of transmission routes in countries at risk of imported disease, it is unclear whether global transmission of the disease can be prevented.


Although many things have been learned in the past few weeks, there are still many key knowledge gaps, including the mode of transmission, the stability of the virus in the environment, the pathogenesis and effective treatments and vaccines. In the current situation, the most important issue is the severity of the disease. It is worth noting that in the early days of the H1N1 influenza pandemic in 2009, reported case deaths were estimated to be as high as 10%. However, population-based sera epidemiological studies stratified by age show that the true overall case mortality rate is about 0.001%. Therefore, serum epidemiological studies are needed to reliably estimate the true severity of the disease. Past infections may also translate into population immunity, which is data that needs to be considered in the future transmission model of this virus. It should be noted that MERS-CoV infection or MERS disease does not always result in a detectable antibody response. If SARS-CoV-2 infection has a similar antibody reaction kinetics as MERS-CoV infection, then this may have an impact on serum epidemiology and population immunity. Therefore, it is urgent to study the antibody dynamics of SARS-CoV-2 and the dynamics of cell-mediated immune response.


参考资料:

Leo L. M. Poon et al. Emergence of a novel human coronavirus threatening human health. Nature Medicine, 2020, doi:10.1038/s41591-020-0796-5.