Advertisement
  • Loading metrics

SARS-CoV-2 infection in China—Before the pandemic

  • Huiying Liang ,

    Contributed equally to this work with: Huiying Liang, Lingling Zheng

    Affiliations Department of Clinical Data Center, The Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China, The Guangdong Provincial Children's Medical Research Center, Guangzhou, China

  • Lingling Zheng ,

    Contributed equally to this work with: Huiying Liang, Lingling Zheng

    Affiliation Department of Clinical Data Center, The Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

  • Huimin Xia ,

    huiminxia@hotmail.com (HX); tangjinling@gwcmc.org (JT)

    Affiliations Department of Clinical Data Center, The Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China, The Guangdong Provincial Children's Medical Research Center, Guangzhou, China, The Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou, China

  • Jinling Tang

    huiminxia@hotmail.com (HX); tangjinling@gwcmc.org (JT)

    Affiliations Department of Clinical Data Center, The Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China, Department of the School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, China

SARS-CoV-2 infection in China—Before the pandemic

  • Huiying Liang, 
  • Lingling Zheng, 
  • Huimin Xia, 
  • Jinling Tang
PLOS
x

Abstract

In order to rapidly inform polices in the international response to the ongoing pandemic of coronavirus disease 19 (COVID-19), we summarize in this review current evidence on epidemiological and clinical features of the infection, transmission routes, problems of nucleic-acid testing, the epidemiological trend in China and impact of interventional measures, and some lessons learned. We concluded that the epidemic is containable with traditional nonpharmacological interventions, mainly through social distancing and finding and isolating suspected patients and close contacts. Nonpharmacological interventions are the only effective measures currently accessible and have suppressed some 90% of the infections in China. Close contacts are the major mechanism of transmission, which makes it possible to control this epidemic through nonpharmacological methods. Nucleic-acid testing alone may miss some 50% of infected patients, and other methods such as chest computerized tomography (CT) or serology should be considered to supplement molecular testing. The development of vaccines and drugs is important, but hesitation to make use of nonpharmacological interventions may mean missing golden opportunities for effective actions.

Author summary

In particular, we summarize the origin of the pathogen, epidemiological and clinical features of the infection, transmission routes and transmissibility, problems of nucleic-acid testing and diagnostic criteria, the epidemiological trend in China and its relation to interventional measures, and special issues including infection in doctors and children and the role of vaccines versus traditional nonpharmacological interventions in control of the epidemic. Importantly, evidence clearly suggests the following:

  1. The epidemic is containable with traditional nonpharmacological interventions, largely by social distancing and testing and isolation of suspected patients and close contacts.
  2. Nonpharmacological interventions are the most immediately accessible effective measures and have helped suppress some 90% of infections in China.
  3. Close contacts through droplets and fomites are the major mechanism of transmission, and asymptomatic infections and aerosols are unlikely important in spreading the virus. This is a major feature of the virus and explains why it is containable through nonpharmacological methods.
  4. Nucleic-acid testing alone may miss many truly infected patients, and chest CT should always be used if available to supplement molecular testing.
  5. Development of vaccines and drugs are important, but any hesitation to use nonpharmacological interventions may mean missing golden opportunities for useful actions against the epidemic.

Introduction

In December 2019, a series of patients with pneumonia of unknown etiology were noted in Wuhan, Hubei Province, China [1,2]. It was soon confirmed to be a highly contagious infectious disease caused by a new virus now known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is similar to the coronavirus responsible for Severe Acute Respiratory Syndrome (SARS) [3,4]. Before March 2020, the epidemic was largely confined to China [5], and massive measures were taken to combat it [6]. It is now steadily abating in China but growing at a considerable pace outside, forming a worldwide pandemic inflicting over 180 countries [5]. The total number of cases reported outside China has surpassed China on 16 March, increasing at a rate of 20% daily in the past 30 days in developed countries [5]. We summarized the epidemiological and clinical features of the disease and control measures and their impact in China with the objective of informing international planning on next steps in the response to the ongoing epidemic.

Pathogen

The pathogen of the pneumonia was confirmed on January 7, 2020 to be a new human-infecting coronavirus [24,7], which was first named 2019 novel coronavirus (2019-nCoV) by the World Health Organization [8] and SARS-CoV-2 as preferred by the International Committee on Taxonomy of Viruses [9]. Genetically, 2019-nCoV belongs to the coronavirus family, which includes SARS and Middle East Respiratory Syndrome (MERS) [2] but is more contagious and less lethal than the latter two [10,11]. The virus was found to be 79.6% genetically identical to SARS-CoV and 96.2% to a bat coronavirus detected in Rhinolophus affinis, a likely reservoir of SARS-CoV-2 [3,7].

Investigations into the intermediate hosts and original epidemic center are inconclusive. Pangolin, a wild animal, was likely an intermediate host responsible for passing the virus from bats to humans, from which a corona virus 91% identical to SARS-CoV-2 at the whole genome level [12] and 93% identical at the spike glycoprotein protein sequences was isolated [13]. Animal–human transmission likely occurred in the Huanan Seafood Wholesale Market in Wuhan, for which 27 (65.9%) of the first 41 coronavirus disease 19 (COVID-19) cases had a history of direct exposure [14]. In addition, the observation that 33 out of 585 environmental samples collected from the market were positive for the nucleic acid of 2019-nCoV further supports this hypothesis.[15] However, the very first patient recorded December 1, 2019 and many early patients did not have any relation to the market, raising questions as to whether the virus originated from there [14,16].

Epidemiology

COVID-19 was highly contagious. The basic reproduction number (R0), the average number of cases a patient can infect during the entire infectious period and in the absence of intervention, is a commonly used measure for the contagiousness of infectious diseases. By using data before January 20, 2020 when no intervention measures were widely taken in China, R0 for 2019-nCoV was estimated around 3.3 (ranging from 1.4–6.5) [17], as compared with 2.7 (2.0–4.0) for SARS [18,19] and below 1 for MERS [20].

Incubation period

The incubation period is approximately 6.0 days (Fig 1), varying from 4.0 to 7.4 days as reported in different studies (Table 1 [2133]). Two weeks are usually used as the longest incubation time for substantiating diagnoses, tracing sources of close contacts, and quarantining suspected patients, although 1.0%–5.8% patients may have an incubation period over 14 days [34,35], which in some may be over 20 days [34,36,37].

thumbnail
Fig 1. Approximate number of days from infection to onset, to first medical visit, to hospitalization, to laboratory diagnosis, and to discharge with COVID-19 patients.

(Table 1 is referred for more details.) CDC, Centers for Disease Control and Prevention; COVID-19, coronavirus disease 19; 2019-nCoV, 2019 novel coronavirus.

https://doi.org/10.1371/journal.pntd.0008472.g001

thumbnail
Table 1. Incubation period, duration of hospitalization, and time from onset to medical visit, hospitalization, and laboratory diagnosis of COVID-19.

https://doi.org/10.1371/journal.pntd.0008472.t001

In addition, the time from onset of illness to hospitalization (equivalent to the time quarantine starts) is the duration in which patients are infectious. It is crucial to reduce this time window for epidemic control. In China, it was on average 14 days before 14 January and reduced to 1 day after 22 January, indicating the considerable impact of measures implemented [4,21]. The average time from hospitalization to discharge is above 12 days [24,32,33], which is important for planning hospital resources, in particular during the peak period of the epidemic. For example, some 2,000 new patients a day needed to be hospitalized in Wuhan in the peak days.

Furthermore, there was an average of 4.5 days between patients’ first medical visit and time of hospitalization. This partly contributed to the delay from onset of illness to hospitalization. The 2-day delay in diagnosis after hospitalization was partly a result of insufficient supply of testing kits but would not cause spreading of virus because patients had already been under quarantine [26]. As a result, the date of public reporting was on average 9 days later than the date of illness onset in China (Fig 1).

Epidemic trend

Fig 2 shows the chronological development of the epidemic and major related events between December 1, 2019 and March 18, 2020. The first case in China occurred December 1, 2019 [14], the first case outside China was diagnosed January 13, 2020 in Thailand, and the first case in another province of China was reported January 19, 2020. The epidemic was steadily escalating until January 20, 2020, before which no systematic, large-scale interventions were embarked upon.

thumbnail
Fig 2. Epidemic curve of the confirmed cases of COVID-19 and time points of major related events.

Daily numbers of confirmed cases are plotted in bars by the date of onset (blue) and by that of diagnosis/reporting (yellow). In the inset are cases in December 2019 (left) and after March 5, 2020 (right). Cases reported outside of China were separately plotted between western countries (red lines) and other countries (brown lines). The daily number of cases by the date of onset were adapted from the data in Fig 3 in the Report of the WHO–China Joint Mission on COVID-19 [6], the rest of the data are from China CDC [5], and the events are from various publications included in this paper. CDC, Centers for Disease Control and Prevention; COVID-19, coronavirus disease 19.

https://doi.org/10.1371/journal.pntd.0008472.g002

January 20, 2020 marked the beginning of the massive combat against the epidemic in China. First of all, COVID-19 was incorporated into class-B notifiable diseases and treated as a class-A disease in action, which was followed by massive nationwide control efforts. Notably, Wuhan, the central epidemic area and a city of 11 million in population, was “locked down” and put under wholesale quarantine on January 23, and all the intercity and soon intracity transports were shut down [6]. More detailed measures are listed in Table 2, including notably identifying and isolating patients and their close contacts, social distancing, mask wearing, closures of public gatherings, quarantine of infected residential areas, and extending the Chinese New Year holidays. Since then, the entire country has come into a public health emergency response unprecedented in its recent history.

If these prevention and control measures were effective, the increasing trend of the daily number of new confirmed cases according to the onset date of illness (blue bars in Fig 2) should be halted and start to decline, forming a peak of this wave of the epidemic. However, this effect would not take place immediately and could only be expected after an incubation period (around 6 days). This is because those infected before January 20 could not be avoided and could continue to infect other people surrounding them in the following 6 days, pushing the peak to January 26. The real epidemic course responded exactly as predicted (blue bars in Fig 2), suggesting that the control efforts such as Wuhan’s lockdown were immediately effective. Since then, the daily number of local cases started to decline and continued until they totally disappeared recently.

Intervention impact

How effective were the actions taken in China? A modeling study published in Lancet January 31, 2020 showed that if there were no reduction in transmissibility of the virus and the mobility of people and the previous momentum of the epidemic continued, the epidemic in Wuhan would peak around late April 2020 with some 30,000 new cases daily. The epidemic in Wuhan actually peaked February 4, 2020, with 1,967 new confirmed cases reported that day (yellow bars in Fig 2). This suggests that the control efforts in China since January 20 may have suppressed the peak number of confirmed cases by over 93.4% and also ended the entire epidemic ahead of the predicted time by approximately 2 months [38]. An article in Science drew a similar conclusion that travel restriction in Wuhan might have reduced 80% of cases outside of China before March 2020 [39]. A more recent Susceptible, Exposed, Infectious, Removed (SEIR) modeling study from Wuhan showed interventions had prevented 94.5% of infections [40].

On March 18, there were 34 cases reported, as compared with 3,893 on the peak day on February 4, representing a 99.1% reduction. All the 34 cases were in fact imported. Since February 9, China has been gradually resuming normal living and working order. The steadily declining trend since then suggests a rebound is unlikely to occur (yellow bars in Fig 2), although China now faces an increasing risk of imported epidemic (Fig 2).

While the epidemic is abating in China, it has taken off outside the country (Fig 2). From February 18 to March 18, the total number of cases in developed countries has jumped from 256 to 86,894, a 339-fold increase or a daily growth rate of 21.4%, very similar to the situation before 20 January 2020 in China. However, a question is raised as to why the epidemic in less developed countries (excluding China) was increasing at a rate only 26.0% that in developed countries during the same period (Fig 2).

Transmission

Routes of transmission

Transmission now is entirely from human to human, but the mechanisms of transmission are less conclusive. Close contact via droplets and fomites are common transmission routes.

However, the virus’ RNA was commonly detected in bronchoalveolar lavage fluids [2,4143], pharyngeal swabs [14,22,24,31,4447], nasal swabs [41,42,45,46], sputum [22,41,42], saliva [41,48], lung tissue [41], and rectal swabs [14,41,42,46,47,49,50] and sometimes also in conjunctival swabs [51], blood [14,41,42,46,52], and urine [41,42,46]. The virus was also successfully isolated through culture from bronchoalveolar lavage fluids [3], saliva [48], urine [53], and rectal specimens [53]. Furthermore, the RNA could persist for as long as 37 days in adults and 51 days in children [32,47]. These findings suggest that the virus can be shed through multiple outlets and other routes of transmission are also possible.

Furthermore, a study in Singapore showed that the virus’ RNA was detectable on various surfaces of rooms where infected patients were quarantined [54]. An American study showed that the virus can survive for 3.0 hours in aerosols and 2–3 days on plastics and metals [55]. These studies raised the possibility of airborne and fecal–mouth transmission. However, such routes of transmission are unlikely common in general public places because thousands of samples from a large range of public environments in Guangzhou failed to show any evidence of the virus [56].

Clustering outbreaks

A prominent feature of COVID-19 is clustering, in particular outbreaks in families, making close contact the most common mechanism of transmission [6,34,57,58]. It was reported that familial clusters contributed up to 78%–85% of confirmed cases in China [6]. An analysis of 377 clusters involving 1,719 cases showed that familial outbreaks accounted for 79% of all clusters, with each causing a median number of 4 cases. Other types of clusters included dining gatherings (10%, each with a median of 5 cases), shopping malls and supermarkets (6%, 13), workplace gatherings (3%, 6), and public transport vehicles (2%, 6) [34]. Clusters in prisons were also reported, with 34–230 cases in an outbreak [59].

Familial contacts are also a high-risk exposure. In general, 1%–5% would be infected after close contact with patients or travel to Hubei epidemic areas [6]. A more recent follow-up study of 4,950 persons with close contact with patients showed the infection risk of high-frequent household contact was as high as 15.8%, as compared with only 1.0% in healthcare settings and 0.1% for patients taking contaminated public transports [60]. Household outbreaks accounted also for 83.7% of cases caused through all transmission forms.

However, the predominance of familial clustering by no means excludes the possibility of effective transmission in the absence of identifiable close contacts. For example, from January 14 to February 18, a series of 40 cases were found associated with a shopping mall in Baodi District of Tianjin, China, which were 31.3% of all the cases in the city [30]. Of the 40 cases, 6 (15.0%) were shop employees and 19 (47.5%) customers, who further caused 15 (37.5%) secondary cases outside the shopping mall. The first case was a shop employee who infected another 5 employees working in adjacent areas mostly with no close-contact opportunities. It is thus postulated that 5 infected employees and 19 infected customers were possibly infected through occasional contacts or even aerosols.

This was further evidenced in the outbreak in the 3,711 passengers on the Diamond Princess cruise ship. The first patient left the ship on January 25 and was diagnosed February 1. Then, the entire ship was put under quarantine on the sea, but the number of new cases continued to rise. As of February 20, 634 cases had been diagnosed, including passengers and cruise staff [61]. Because quarantine was imposed and close contacts were limited, occasional contacts, aerosols, and even the central air conditioning with recirculating air were likely explanations of transmission for many cases.

Transmission during incubation

Continuous nucleic-acid testing in those with close-contact history provided clear evidence that patients shed virus before symptoms appear in both adults and children, pointing to the possibility of transmission during incubation [47,61,62]. Studies also found the serial interval between the first and second generation of COVID-19 cases ranged between 4.0–4.6 days [34,63,64], which is shorter than the average incubation period of 6 days, providing further evidence for transmission during incubation [65].

Evidence is also available from observation of infections directly caused by patients in incubation, but cases were not common. For example, Lancet Infectious Disease reported a familial cluster of 11 cases caused by a case a week before symptoms appeared [66], in addition to other similar reports [67,68].

Transmission from asymptomatic infection

Asymptomatic infection is a great concern for transmission because it is more difficult to discover and control. Asymptomatic infection is referred to infections with the virus that can be confirmed with nucleic-acid or serological testing and may cause radiological and laboratory changes but will never develop symptoms. Cases have been reported in both children and adults who were consecutively nucleic-acid positive but remained completely free of symptoms even 30 days after the last exposure [47,57,62], suggesting transmission from asymptomatic patients could be theoretically possible.

How often does asymptomatic infection exist in all the infected? A modeling study of the outbreak on the Diamond Princess cruise ship showed asymptomatic infection could, in theory, account for 17.9% of all infections [61]. Other modeling studies gave estimates as high as 30.8%–86.0% [40,62,69]. This is, however, in sharp contrast to the empirical observation that only 1.0% were diagnosed purely via viral nucleic-acid testing and completely asymptomatic [70]. Close follow-up of 4,950 close contacts showed 8 (6.2%) of the 129 cases were completely asymptomatic by the end of 14 days’ quarantine [60].

These large different estimates may partly be explained by different definitions for asymptomatic infection, rigorousness in assessing symptoms, and the populations studied. As of March 18, some 700,000 close contacts had been identified and clinically closely observed in China. If 5% of them eventually contracted infection, it was impossible that there were only less than 1,000 asymptomatic patients in the entire country.

Cases infected from asymptomatic infection have also been reported but not common. A follow-up study of 24 patients asymptomatic at diagnosis in Nanjing found 7 were completely asymptomatic throughout, with 1 having caused a familial outbreak [71]. Furthermore, a Journal of the American Medical Association (JAMA) article reported a patient caused a familial cluster of 5 cases but remained asymptomatic and free of any radiological and laboratory alterations for over 19 days when observation ended [72].

How often does asymptomatic infection exist in general populations? In Guangdong, it was found the RNA evidence of SARS-CoV-2 was positive in only 48 in 190,000 outpatients of fever clinics and 3 in 60,000 Hubei returnees [6, 60], suggesting asymptomatic infections be even rarer in general populations, although Hubei may be higher. Large serological studies have yet to be conducted.

In summary, infection via asymptomatic infection is possible but unlikely a common mechanism of transmission. Otherwise, many close contacts would be untraceable, and the epidemic could have not been effectively contained as it is in China and Korea largely by finding and quarantining close contacts through identified patients.

Transmission during convalescence

There is some evidence for persistent positivity for the virus’ nucleic acid in throat swabs and in particular rectal swabs after recovery, which could last as long as 37 to 51 days in adults [32,47]. Interesting cases were reported in a JAMA article that 4-time consecutive-test–negative convalescent patients became positive again 5–13 days later [64]. These findings suggest patients could potentially shed the virus during convalescence but should not be considered direct evidence of replication-competent viruses that can cause further infections. We have not seen reports of people infected by patients in the convalescent period.

Diagnosis

Finding patients early is crucial for control of the epidemic. Because the clinical manifestations of COVID-19 are nonspecific, a definitive diagnosis largely relies on nucleic-acid testing [73,74]. Nucleic-acid testing should be performed on throat swabs and/or rectal swabs in particular during convalescence. Two consecutive samples 48 hours apart can considerably improve sensitivity. Although the nucleic-acid testing provided reliable evidence of infection, evidence of nucleic acid does not necessarily indicate the presence of infectious virus, and a negative result does not necessarily rule out the diagnosis. For highly suspected patients, chest computerized tomography (CT) should be used to supplement nucleic-acid testing. Serum immunoglobulin M (IgM) and IgG tests are now available and can help boost up the detection rate [75] but will be less useful for initiation of treatment and quarantine.

During an epidemic of a highly infectious disease, diagnostic methods with a high sensitivity are preferable, or we may delay both treatment and isolation and cause undesirable consequences. Until February 12, the diagnostic criteria China used required throat swab test be positive by a real-time reverse transcription polymerase chain reaction (RT-PCR). First, this requirement delayed diagnosis of patients for at least 5 days at the early days of the epidemic because of an insufficient supply of testing kits. Second, it had missed many true patients because of the low sensitivity (about 30%–50%) and caused delays in treatment and quarantine [76]. The low sensitivity may have resulted from patients who are not shedding virus or are shedding virus at an undetectable amount in early infection, convalescence, or a silent intermittent-shedding period. The low sensitivity can also be caused by inappropriate methods of collecting samples, sampling sites such as throat swabs instead of bronchoalveolar lavage fluid, and storage and transport of specimens.

The low sensitivity of nucleic-acid testing later turned out to be a serious problem in the epicenter Hubei Province, in particular in Wuhan. Studies found that in people highly suspected to have COVID-2019, chest CT evidence of viral pneumonia often preceded PCR evidence and appeared in 97% of early infections [77.78]. Consequently, China had to revise the diagnostic criteria so as to include all clinically suspected patients [74]. The new criteria were used only for 4 days between February 12–15. As a result, a total of 18,431 patients (excluded in Fig 2) were clinically diagnosed, hospitalized, and treated free of cost and put under quarantine. This helped greatly in clearing up the potential sources of infection in the population. A lesson learned is that heavy reliance on viral evidence for diagnosis gained in accuracy but caused delays in quarantine and treatment.

Clinical features

COVID-19 is a new infectious disease, and all are susceptible. Of the 44,672 confirmed cases before February 11, 2020, patients were between the age of 30–79 years [70]. The majority were diagnosed in Hubei Province (75%), and most early cases reported Wuhan-related exposures (86%). Eighty-one percent were mild or moderate cases (for having mild pneumonia or lack of pneumonia). However, 14% were severe (for having dyspnea, respiratory frequency 30/min, blood oxygen saturation 93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300, and/or lung infiltrates >50% within 24 to 48 hours), and 5% were critical (for having respiratory failure, septic shock, and/or multiple organ dysfunction or failure).

The overall case fatality was 2.3%. No deaths occurred in the group aged 9 years and younger, but the fatality was 8.0% in cases aged 70–79 years and 14.8% in those aged 80 years and older. No deaths were reported among mild, moderate, or severe cases; all deaths occurred in critical cases, showing a fatality of 49.0%. The fatality was elevated among those with preexisting comorbidities: 10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer. Fatality also differed considerably by area [70]. As of March 19, fatality was 5.0% (2,498/50,005) in Wuhan, 3.6% (634/17,759) in Hubei excluding Wuhan, and 0.88% (116/13,167) in China excluding Hubei [5]. In contrast, in Italy, 12% of all detected COVID-19 cases and 16% of all hospitalized patients were admitted to the intensive care unit, and the case fatality was 5.8%, double that in China [79]. In addition, high Sequential Organ Failure Assessment (SOFA) score and d-dimer were also found related to poor prognoses [32].

Table 3 summarizes clinical, radiological, and laboratory features of 2019-nCoV patients at admission reported in 5 major relevant studies. A large number of patients also had common morbidities like cardiovascular diseases, hypertension, and diabetes. Common symptoms included fever, cough, dyspnea, sputum, myalgia, fatigue, and anorexia. Most patients showed radiological abnormalities, but only 20% demonstrated ground-glass opacities. Some patients showed alternations in lymphocyte counts, procalcitonin, aspartate aminotransferase (AST), and C-reactive protein. Acute respiratory distress syndrome (ARDS), acute kidney injury, acute cardiac injury, coinfections, and shock also existed but were not common.

thumbnail
Table 3. Demographics underlying medical conditions, symptoms and signs, laboratory findings, radiological alterations, treatments, complications, and prognoses with COVID-19 from 5 studies of 1,439 patients in Chinaa.

https://doi.org/10.1371/journal.pntd.0008472.t003

No antiviral agents have been approved by regulatory agencies for the treatment of COVID-19, and the clinical management of the infection was supportive care. Antiviral drugs, antibiotic treatments, Chinese herbal medicine, and corticosteroids were commonly used, and extracorporeal membrane oxygenation (ECMO) was applied to less than 5% (Table 3), but their effectiveness is largely unknown. Antimicrobial drugs were recommended based on their effectiveness in preventing infections before exposure or after exposure to microbial pathogens and in reducing the risk of secondary spread of infection [80]. A recent clinical trial showed that in hospitalized adult patients, no additional benefit on major outcomes was observed from lopinavir–ritonavir on top of standard care [81]. Against general evidence of no effect in treating respiratory infection due to respiratory syncytial virus (RSV), influenza, SARS-CoV, or MERS-CoV [82], corticosteroids were commonly used in treating COVID-19.

Overall, considering the clinical features of the disease, it is advisable that mild or moderate patients be cared for and quarantined at home when hospital resources are tight.

Miscellaneous and lessons learned

Infections in children

Children are believed to be less likely to be infected. A report of the earliest 425 cases found no children under the age of 15 years were infected [21]. This is sharply disproportionate to the percentage of children of the same age band (17.8%) in the Chinese general population [83]. A more recent report showed that 2.2% of the confirmed cases (965/44,672) were under the age of 20 years as compared to 24.1% of children of this age band in the general population [70]. Furthermore, a comparison study showed that the infection rate was 3.5% (111/3,174) in exposed adults and 1.3% (10/745) in exposed children, suggesting if exposed, adults are 2.7 more likely to be infected than children (P = 0.002) [47]. If infected, compared with adult patients, pediatric cases in general are clinically mild and less likely to show typical radiological alterations in the lungs [47,8486].

Sparse data are available on intrauterine or perinatal transmission. In 2 reports including a total of 18 pregnant women with suspected or confirmed COVID-19 pneumonia, there was no molecular evidence of transmission from mother to neonate. In 2 infected neonatal cases documented so far [87], one was diagnosed on the seventeenth day of birth and was likely infected because of close contact with the mother and maternity matron, both of whom were infected before the child was born [88]. The other case was diagnosed 36 hours after birth; the source and time of transmission were unclear.

Infections in health workers

Among the first 44,672 cases, a total of 1,716 were health workers (3.8%), 1,080 of whom were in Wuhan (63%), of which 40% of the infections occurred in hospitals and the rest in general communities [6,70]. Interestingly, none of the infections occurred in the 42,000 physicians who were sent out to support Hubei. Overall, 14.8% of confirmed cases among health workers were classified as severe or critical, and 5 died [70].

The outbreaks in health workers at the early stage of SARS and COVID-19 epidemics are a feature in the 2 epidemics, suggesting that alertness to infectious diseases and protection is not sufficiently high among clinicians at the early stage of the epidemic. They are also partly because hospitals were in general unprepared for highly contagious infectious diseases and taking care of a large increase in the number of patients. For example, as the pandemic accelerated, access to personal protective equipment for health workers was a problem. Some medical staff were waiting for equipment while already seeing patients who might be infected or were supplied with equipment that might not meet requirements [89]. Furthermore, during the peak period, a huge number of fever patients poured into outpatient departments of hospitals and made them a major place for spreading the virus. On the other hand, hospitals incapable of quickly admitting all the patients left thousands of them in the communities and increased the risk of transmission. The situation was alleviated after some 60,000 hospital beds were urgently created in Wuhan and 42,000 doctors from other provinces were sent out to Hubei.

Vaccine or quarantine?

What we believe largely determines how we act. The remarks of Dr. Bruce Aylward, WHO’s Secretary General, on February 24 [90] may reflect what we believe today in confronting this new deadly disease: “In the world of preparedness and planning, I suffer the same biases as or maybe error of thinking as many people… we don’t have a vaccine, we don’t have a therapeutic.” How can we defeat this epidemic?

Indeed, it was believed that actions were not sufficiently fast at the early stage of the epidemic in China, which may partly be a result of our societal belief in new scientific methods such as confirming the pathogen via virologic diagnostics, antiviral drugs, and vaccines. However, the success of these research efforts is not immediately foreseeable but will compete for the public’s attention and resources with the epidemiological and clinical investigations that are immediately important for formulating preventive and treatment policies. For example, the specific viral diagnostic testing kits for 2019-nCoV were already available January 12, but whether or not the virus could transmit among humans was still debated until February 20. Later, the PCR method tended to miss diagnoses and, in a sense, facilitated the spread of the disease.

Conclusions

COVID-19 is highly contagious but can be effectively contained with quick and determined traditional nonpharmacological measures such as isolation and social distancing, as is demonstrated in China and Korea. The time window for critical early action may be missed if we hold that a large number of asymptomatic or undocumented infections exist to facilitate the rapid dissemination of infection so that the epidemic is beyond control. Given the increasing momentum of the pandemic, millions of infections and many deaths could soon occur if control measures were not put in order in time and with resolve.

Acknowledgments

We thank Feng Sha, Shuai Huang, Xiujuan Chen, Kang Qin, Lei Chen, and Dong Liu for collecting data and giving comments.

References

  1. 1. Wuhan Municipal Health Commission. Report of clustering pneumonia of unknown etiology in Wuhan City [Internet]. 2019 [cited 2019 Dec 31]. Available from: http://wjw.wuhan.gov.cn/xwzx_28/gsgg/202004/t20200430_1199588.shtml.
  2. 2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727–33. pmid:31978945
  3. 3. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–3. pmid:32015507
  4. 4. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al.A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265–9. pmid:32015508
  5. 5. Chinese Center for Disease Control and Prevention. Distribution of novel coronavirus pneumonia [Internet]. 2019 [cited 2020 Feb 15]. Available from: http://2019ncov.chinacdc.cn/2019-nCoV/index.html.
  6. 6. World Health Organization. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) [Internet]. 2020 [cited 2020 Feb 16]. Available from: https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf.
  7. 7. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565–74. pmid:32007145
  8. 8. World Health Organization. Novel coronavirus (2019-nCoV) [Internet]. 2020 [cited 2020 Feb 15]. Available from: https://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/novel-coronavirus-2019-ncov.
  9. 9. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;(32123347):2058–5276.
  10. 10. Li Liming. [An update on the epidemiological characteristics of novel coronavirus pneumonia (COVID-19)]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(2):139–44. pmid:32057211
  11. 11. Chen J. Pathogenicity and transmissibility of 2019-nCoV-A quick overview and comparison with other emerging viruses. Microbes Infect. 2020;22(2):69–71.
  12. 12. Zhang T, Wu Q and Zhang Z, Probable pangolin origin of 2019-nCoV associated with outbreak of COVID-19. Current Biology. 2020;30(7): 1346–1351.e2. pmid:32197085
  13. 13. Liu Z, Xiao X, Wei X, Li J, Yang J, Tan H, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2. J Med Virol 2020;13(1):26–31.
  14. 14. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. pmid:31986264
  15. 15. Chinese Center for Disease Control and Prevention. 585 environmental samples from the South China Seafood Market in Wuhan, Hubei Province, China. 2020 [cited 2020 Jan 27]. Available from: http://www.chinacdc.cn/yw_9324/202001/t20200127_211469.html.
  16. 16. Cohen J. Wuhan seafood market may not be source of novel virus spreading globally. Science AAAs. Epub 2020 Jan 26.
  17. 17. Liu Y, Gayle AA, Wilder-Smith A, Rocklov J. The reproductive number of COVID-19 is higher compared to SARS coronavirus. Journal of travel medicine. 2020;27(2): taaa021. pmid:32052846
  18. 18. Riley S, Fraser C, Donnelly CA, Ghani AC, Abu-Raddad LJ, Hedley AJ, et al. Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions. Science. 2003;300(5627):1961–6. pmid:12766206
  19. 19. World Health Organization. Consensus document on the epidemiology of severe acute respiratory syndrome (SARS). 2003 [cited 2020 Feb 15]. Available from: https://www.who.int/csr/sars/en/WHOconsensus.pdf?ua=1.
  20. 20. World Health Organization. WHO MERS Global Summary and Assessment of Risk. 2018 [cited 2020 Feb 15]. Available from: https://www.who.int/csr/disease/coronavirus_infections/risk-assessment-august-2018.pdf?ua=1&ua=1&ua=1.
  21. 21. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia. N Engl J Med. 2020;382: 1199–1207. pmid:31995857
  22. 22. Xu X, Wu X, Jiang X, Xu K, Ying L, Ma C, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368: m606. pmid:32075786
  23. 23. Backer JA, Klinkenberg D, Wallinga J. Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20–28 January 2020. Euro Surveill. 2020;25(5): 2000062.
  24. 24. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382: 1708–1720. pmid:32109013
  25. 25. Linton NM, Kobayashi T, Yang Y, Hayashi K, Akhmetzhanov AR, Jung SM, et al. Incubation Period and Other Epidemiological Characteristics of 2019 Novel Coronavirus Infections with Right Truncation: A Statistical Analysis of Publicly Available Case Data. J Clin Med. 2020;9(2): 538.
  26. 26. Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z, et al. Characteristics of COVID-19 infection in Beijing. The Journal of infection. 2020;80(4): 401–406. pmid:32112886
  27. 27. Bi Q, Wu Y, Mei S, Ye C, Zou X, Zhang Z, et al. Epidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts. medRxiv 20028423 [Preprint]. 2020.
  28. 28. Wang P, Lu J, Jin Y, Zhu M, Wang L, Chen S. Epidemiological characteristics of 1212 COVID-19 patients in Henan, China. medRxiv 20026112 [Preprint]. 2020.
  29. 29. Sun K, Chen J, Viboud C. Early epidemiological analysis of the 2019-nCoV outbreak based on a crowdsourced data. medRxiv 20019935 [Preprint]. 2020.
  30. 30. Wu W, Li Y, Wei Z, Zhou P, Lyu L, Zhang G, et al. [Investigation and analysis on characteristics of a cluster of COVID-19 associated with exposure in a department store in Tianjin]. Zhonghua Liu Xing bing Xue Za Zhi. 2020;41: 489–93. pmid:32133830
  31. 31. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11): 1061–1069.
  32. 32. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020;395(10229): 1054–1062. pmid:32171076
  33. 33. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA internal medicine. 2020;180(7): 1–11. pmid:32167524
  34. 34. Yang H, Xu J, Li Y, Jin Y, Chen S, Zhang R, et al. [The preliminary analysis on the characteristics of the cluster for the Corona Virus Disease]. Zhonghua Liu Xing bing Xue Za Zhi. 2020;41:623–8. pmid:32145716
  35. 35. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020;172(9): 577–582. pmid:32150748
  36. 36. Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. Journal of Medical Virology. 2020;92(6):568–576. pmid:32134116
  37. 37. Cai J, Sun W, Huang J, Gamber M, Wu J, He G. Indirect Virus Transmission in Cluster of COVID-19 Cases, Wenzhou, China, 2020. Emerging Infectious Disease journal. 2020;26(6): 1343–1345.
  38. 38. Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet. 2020; 395(10225): 689–97. pmid:32014114
  39. 39. Chinazzi M, Davis J, Ajelli M, Gioannini C, Litvinova M, Merler S, et al. The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science. 2020;368(6489): eaba9757.
  40. 40. Wang C, Liu L, Hao X, Guo H, Wang Q, Huang J, et al. Evolving Epidemiology and Impact of Non-pharmaceutical Interventions on the Outbreak of Coronavirus Disease 2019 in Wuhan, China. medRxiv 20030593 [Preprint]. 2020.
  41. 41. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020;323(18): 1843–1844. pmid:32159775
  42. 42. Ling Y, Xu SB, Lin YX, Tian D, Zhu ZQ, Dai FH, et al. Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J (Engl). 2020;133(9): 1039–1043. pmid:32118639
  43. 43. Shen Z, Xiao Y, Kang L, Ma W, Shi L, Zhang L, et al. Genomic diversity of SARS-CoV-2 in Coronavirus Disease 2019 patients. Clin Infect Dis. 2020: ciaa203. pmid:32129843
  44. 44. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395(10223):507–13. pmid:32007143
  45. 45. Qiu J, Shen B, Zhao M, Wang Z, Xie B, Xu Y. A nationwide survey of psychological distress among Chinese people in the COVID-19 epidemic: implications and policy recommendations. General psychiatry. 2020;33(2): e100213. pmid:32215365
  46. 46. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020;382(10): 929–36. pmid:32004427
  47. 47. Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nature Medicine. 2020;26: 502–505. pmid:32284613
  48. 48. To KK, Tsang OT, Chik-Yan Yip C, Chan KH, Wu TC, Chan JMC, et al. Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis. 2020: ciaa149. pmid:32047895
  49. 49. Tang A, Tong ZD, Wang HL, Dai YX, Li KF, Liu JN, et al. Detection of Novel Coronavirus by RT-PCR in Stool Specimen from Asymptomatic Child, China. Emerg Infect Dis. 2020;26(6): 1337–1339. pmid:32150527
  50. 50. Xie C, Jiang L, Huang G, Pu H, Gong B, Lin H, et al. Comparison of different samples for 2019 novel coronavirus detection by nucleic acid amplification tests. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases. 2020;93: 264–7.
  51. 51. Zhou Y, Zeng Y, Tong Y, Chen C. Ophthalmologic evidence against the interpersonal transmission of 2019 novel coronavirus through conjunctiva. medRxiv 20021956 [Preprint]. 2020.
  52. 52. Zhang R. [The virus is found in the blood and feces of severely ill patients, which may lead to other ways of virus transmission.] People's Daily [Internet]. 2020 [cited 2020 Feb 13]. Available from: https://dxy.com/column/27681.
  53. 53. Zhong N. The novel coronavirus was isolated from the patient's urine. Information Office of Guangzhou Municipal People's Government [Internet]. 2020 [cited 2020 Feb 27]. Available from: http://special.gznews.gov.cn/2020/node_5147/index.shtml.
  54. 54. Ong SWX, Tan YK, Chia PY, Lee TH, Ng OT, Wong MSY, et al. Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From a Symptomatic Patient. JAMA. 2020;323(16): 1610–1612. pmid:32129805
  55. 55. van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020;382(16): 1564–1567. pmid:32182409
  56. 56. Guangzhou CDC. SARS-CoV-2 monitoring results of public places in Guangzhou [Internet]. 2020 [cited 2020 Mar 17]. Available from: https://mp.weixin.qq.com/s/-ze2sZMDJJ-9oYLi4WtmlA.
  57. 57. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395(10223): 514–23. pmid:31986261
  58. 58. Pung R, Chiew CJ, Young BE, Chin S, Chen MIC, Clapham HE, et al. Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures. Lancet. 2020;395(10229): 1039–1046. pmid:32192580
  59. 59. Armstrong S. The prison service is still failing inmates' healthcare needs. BMJ. 2020;368: m724. pmid:32102792
  60. 60. Luo L, Liu D, Liao X, Wu X, Jing Q, Zheng J, et al. Modes of Contact and Risk of Transmission in COVID-19: A Prospective Cohort Study 4950 Close Contact Persons in Guangzhou of China [Preprint]. 2020 [cited 2020 Feb 15]. Available from: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3566149.
  61. 61. Kenji Mizumoto, Katsushi Kagaya, Alexander Zarebski, Gerardo Chowell. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill. 2020;25(10): 2000180.
  62. 62. Nishiura H, Kobayashi T, Suzuki A, Jung SM, Hayashi K, Kinoshita R, et al. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases. 2020;94: 154–155. pmid:32179137
  63. 63. Nishiura H, Linton NM, Akhmetzhanov AR. Serial interval of novel coronavirus (COVID-19) infections. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases. 2020;93: 284–286. pmid:32145466
  64. 64. Zhao S, Cao P, Gao D, Zhuang Z, Cai Y, Ran J, et al. Serial interval in determining the estimation of reproduction number of the novel coronavirus disease (COVID-19) during the early outbreak. Journal of travel medicine. 2020;27(3): taaa033. pmid:32163140
  65. 65. Gao W, Li L. Advances on presymptomatic or asymptomatic carrier transmission of COVID-19. Zhonghua liu xing bing xue za zhi. 2020;41: 485–8.
  66. 66. Huang R, Xia J, Chen Y, Shan C, Wu C. A family cluster of SARS-CoV-2 infection involving 11 patients in Nanjing, China. Lancet Infect Dis. 2020;20(5): 534–535. https://doi.org/10.1016/S1473-3099(20)30147-X.
  67. 67. Yu P, Zhu J, Zhang Z, Han Y, Huang L. A familial cluster of infection associated with the 2019 novel coronavirus indicating potential person-to-person transmission during the incubation period. J Infect Dis. 2020;221(11): 1757–1761. pmid:32067043
  68. 68. Li P, Fu JB, Li KF, Chen Y, Wang HL, Liu LJ, et al. Transmission of COVID-19 in the terminal stage of incubation period: a familial cluster. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases. 2020;96: 452–453. pmid:32194239
  69. 69. Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science. 2020;368(6490): 489–493. pmid:32179701
  70. 70. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13): 1239–1242. pmid:32091533
  71. 71. Hu Z, Song C, Xu C, Jin G, Chen Y, Xu X, et al. Clinical Characteristics of 24 Asymptomatic Infections with COVID-19 Screened among Close Contacts in Nanjing, China. Sci China Life Sci. 2020;63(5): 706–711. pmid:32146694
  72. 72. Bai Y, Yao L, Wei T, Tian F, Jin D-Y, Chen L, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA. 2020;323(14): 1406–1407. pmid:32083643
  73. 73. World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance [Internet]. 2020 [cited 2020 Feb 15]. Available from: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected.
  74. 74. Liang X, Feng Z, Li L. Guidance for Corona Virus Disease 2019: Prevention, Control, Diagnosis and Management. Beijing, China: People’s Medical Publishing House; 2020.
  75. 75. Xu W, Li J, He X, Zhang C, Mei S, Li C, et al. [The diagnostic value of joint detection of serum IgM and IgG antibodies to 2019-nCoV in 2019-nCoV infection]. Zhonghua Jianyan Yixue Zazhi. 2020;43: 230–233.
  76. 76. Zheng H, Li Y. Problems and countermeasures in nucleic acid detection of novel coronavirus. Clinical Laboratory [Internet]. 2020 [cited 2020 March 15]. Available from: https://www.ddm360.com/article/detail/1060.
  77. 77. Xie X, Zhong Z, Zhao W, Zheng C, Wang F, Liu J. Chest CT for Typical 2019-nCoV Pneumonia: Relationship to Negative RT-PCR Testing. Radiology. 2020: 200343. pmid:32049601
  78. 78. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020: 200642. pmid:32101510
  79. 79. Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. 2020;323(16): 1545–1546. pmid:32167538
  80. 80. Mitjà O, Clotet B. Use of antiviral drugs to reduce COVID-19 transmission. Lancet Global Health. 2020;8(5): e639–e640. pmid:32199468
  81. 81. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19): 1787–1799. pmid:32187464
  82. 82. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223): 473–475. pmid:32043983
  83. 83. National Bureau of Statistics. Sixth census data in China. Beijing, China: National Bureau of Statistics; 2011.
  84. 84. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. Pediatrics. 2020: e20200702. pmid:32179660
  85. 85. Liu W, Zhang Q, Chen J, Xiang R, Song H, Shu S, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med. 2020;382(14): 1370–1371. pmid:32163697
  86. 86. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 Infection in Children. The New England journal of medicine. 2020;382(17): 1663–1665. pmid:32187458
  87. 87. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020;395(10226): 809–815. pmid:32151335
  88. 88. China National Report. A newborn was diagnosed as COVID-19 30 hours after birth [Internet]. 2020 [cited 2020 Feb 5]. Available from: http://www.cnr.cn/hubei/yuanchuang/20200205/t20200205_524961963.shtml.
  89. 89. The Lancet. COVID-19: protecting health-care workers. Lancet. 2020; 395(10228): 922.
  90. 90. World Health Organization. Press Conference of WHO-China Joint Mission on COVID-19 Date: February 24th, 2020 (evening) [Internet]. 2020 [cited 2020 Feb 34]. Available from: https://www.who.int/docs/default-source/coronaviruse/transcripts/joint-mission-press-conference-script-english-final.pdf?sfvrsn=51c90b9e_10.