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Severe acute respiratory syndrome (SARS), a viral respiratory illness caused by the coronavirus SARS-CoV, was possibly the first globally significant occupational disease to emerge in the 21st century, making healthcare work potentially hazardous. This was indicated by the high incidence of SARS observed among health care workers (HCWs) in the epidemic of SARS, especially during its earlier stages. In China, from a total of 5323 SARS cases, 966 (over 18%) were HCWs, and in the early period of the SARS epidemic, near 90% of the SARS patients were frontline HCWs. In Hong Kong, a total of 384 (22.1%) of 1739 suspected or confirmed SARS patients were hospital workers. Generally, SARS outbreaks first originated in hospitals where SARS patients were treated and subsequently spread to communities from there.
Several studies indicated that HCWs coming into direct or indirect contact with SARS patients in wards had a greatly increased risk of contracting SARS-Cov, despite some strict infection control measures being taken. A similar situation also arose in the Second Affiliated Hospital and the Third Affiliated Hospital of Sun Yat-sen University during the epidemic of SARS in 2003. A total of 846 HCWs worked on the frontline of caring for SARS patients in the two affiliated hospitals and 112 of them contracted SARS during this time. Throughout the whole period of the SARS epidemic, a series of infection control and protective measures were employed in the two affiliated hospitals. But, why were some of HCWs infected by SARS, and some of them were not? The objective of this study was to determine which preventive measures used were effective in protecting HCWs from SARS, and which were not effective. To answer this question, we conducted a retrospective study of HCWs who worked at the frontline in the two affiliated hospitals during the SARS epidemic.
SARS-CoV infection results in a severe respiratory disease. It causes significant nosocomial infection and requires aggressive infection control practices rarely used for other causes of atypical pneumonia. Laboratory confirmation of SARS is crucial in the management of patients presenting with pneumonia, particularly as the clinical features of SARS make it difficult to distinguish from other causes of atypical pneumonia. Molecular methods for SARS diagnosis are useful, although their value is affected by the observation that maximal viral shedding occurs after the first week of illness rather than at the initial clinical presentation. The SARS outbreak was characterized by high infection rates in healthcare workers; patient self-collected specimens such as throat washes or feces, or serum may pose less risk to healthcare workers, particularly in the context of concerns about nosocomial acquisition. Although NPAs and other lower respiratory tract samples are the sample of choice for suspected respiratory viral infections, patient self-collected specimens are suitable for RT-PCR. Thus they offer diagnostic value, especially in SARS where the peak of viral shedding is after the first week of illness, and this sampling approach may reduce the safety issues of healthcare workers collecting NPAs. Patient self-collected specimens may be less appropriate for common seasonal respiratory virus infections such as influenza, where viral shedding is maximal at clinical presentation and virus is rarely detected outside the respiratory tract. Accurate and rapid laboratory diagnosis will become even more important as SARS becomes less common, or in the event of new outbreaks of SARS, especially if influenza or other seasonal respiratory viruses are co-circulating.
The clinical features of this cohort of 271 patients managed at a single institution were similar to those reported elsewhere, although diarrhea was present in only 11% of patients compared to rates of 20–73% reported in studies from Hong Kong and Canada. Like other SARS outbreaks, many cases (41.3%) were acquired after exposure in the hospital environment, with healthcare workers providing 34% of cases at this institution. Of note was a case of SARS possibly acquired in a diagnostic laboratory. There have since been a number of cases acquired in research laboratories.
Detection of SARS-CoV RNA by RT-PCR is only moderately useful in the early diagnosis of SARS, as the maximal viral load and RT-PCR sensitivity occurs in the second week of illness. In addition, the sensitivity of SARS-CoV RT-PCR on specimens collected from different sites and at different time points in the illness varies. Testing more than one clinical specimen increases the likelihood of obtaining a positive RT-PCR result. In one large study, 60% of patients with clinical SARS had a positive SARS-CoV RT-PCR in one or more clinical specimens, with the highest detection rates in sputum (55.6%), NPAs (29.6%) and nose/throat swabs (20%) collected within the first 5 days of illness. We found that the likelihood of a positive SARS-CoV RT-PCR was similar in serum (54.3%) and throat washes (56.6%) in the first 9 days of illness. We found the peak of SARS-CoV detection in throat washes to be between days 5 to 14, where 60.8% (42/69) of samples were positive, similar to reported rates in other respiratory specimens. The viral loads in throat washes decreased over time and were at levels between those in feces and sera at similar time points.
In other studies, throat swabs were RT-PCR positive in 37.5% of probable SARS cases, reaching 50–60% on days 7–10, and consistent with earlier studies showing peaks of virus shedding in the respiratory tract in the second week of illness. High viral loads were seen in NPAs in 14 patients with SARS, mainly in the second week of illness. The use of patient self-collected throat washings may reduce risks to healthcare workers, although lower respiratory tract samples such as sputum, NPAs or bronchoalveolar lavage fluid are likely to have higher viral loads and offer increased likelihood of SARS-CoV detection by RT-PCR. We were unable to correlate viral loads in the various clinical samples with ability to isolate virus or transmission to other people; whether viral load in the respiratory tract correlates with 'super-shedding' events is uncertain.
Although overall SARS-CoV detection rates and viral load in throat washes and stools were higher than in the serum, serum SARS-CoV RT-PCR is a useful investigation early in the illness as we found that 50% of sera had SARS-CoV detected in the first four days of illness. One study of sera from 8 probable SARS patients found a detectable SARS-CoV load ranging from 2 × 103 to 1 × 104 copies/ml serum in 50% of the samples, but not after 12 days after onset. Of interest was that occasional serum samples from individuals remained SARS-CoV RT-PCR positive (with moderate viral loads) over three weeks after onset of illness, a feature noted in another study.
High rates of SARS-CoV RT-PCR detection (as high as 86.3% between days 10–19) and high viral loads were found in fecal samples in the second to fourth weeks of disease. Rates of SARS-CoV detection in fecal samples began to decrease after one month, although many stools were still SARS-CoV RNA positive 40 days or more after the onset of the clinical illness. The SARS-CoV load in fecal samples collected after 40 days were higher than the peak load seen in sera collected early in disease, and comparable to the viral load in throat washes in the second week of illness. Both lower (27% in fecal samples collected 11–20 days after onset) and similar high detection rates (over 80% in stools collected 11–16 days after onset) have been reported elsewhere, as have fecal samples positive 40 days or more after onset. Despite the high SARS-CoV load in feces, diarrhea was not a prominent clinical feature in this cohort. Long-term fecal viral shedding may be an additional source of community spread of SARS, although the infectivity of feces may be better assessed with virus isolation.
Direct comparisons of the sensitivity and specificity of RT-PCR for the detection of SARS-CoV are hampered by the use of different types of clinical specimens, RNA extraction procedures and different RT-PCR techniques. The first published interlaboratory comparison showed sensitivities of 61% and 68% for 72 NPAs, 65% and 72% for 54 throat swabs, 50% and 54% for 78 urine samples and 58% and 63% for 19 stool specimens, with an overall specificity of 100%. To date, no significant differences in the sensitivity and specificity of various commercial and in-house RT-PCR or other molecular assays have been reported.
In mid-May 2003, about 4 months after the initial SARS outbreak in Guangzhou, a retrospective study was conducted in HCWs working at the frontline of the SARS epidemic, providing primary care in the Second Affiliated Hospital and the Third Affiliated Hospital of Sun Yat-sen University, where the first and second outbreak of SARS among HCWs occurred in the early stage of SARS epidemic in Guangzhou. Among a total of 846 frontline HCWs who tended to SARS patients from the two hospitals, 758 (89.2%) who were on duty during the investigation were surveyed, and they included HCWs from all departments involved in the care of SARS patients in the two hospitals. But, those who were off-duty during the survey were excluded. During the SARS epidemic, a total of 112 HCWs working on the frontline were diagnosed suffering from "SARS" according to a case definition of SARS by the Ministry of Health, China, and 90 of them were successfully interviewed, giving a response rate of 80.4% (90/112). Written informed consent was obtained from all the participants prior to enrollment after a detailed explanation of the study objectives and requirements of the survey. The Ethical Committee of the Sun Yat-sen University approved the study.
On 22 September 2012, the WHO was informed by the UK of a case of acute respiratory syndrome with renal failure. The patient had a travel history to the Kingdom of Saudi Arabia, where a 60 year-old Saudi national died from a similar disease earlier in 2012. The causative pathogen, a novel human Betacoronavirus (HCoV-EMC), was quickly identified from the sputum samples of the earlier case and the gene sequence of this virus was 99.5% identical to that of the virus isolated from clinical samples of the later case.
The outbreak of HCoV-EMC infection in Saudi Arabia has raised great concerns about the potential pandemic of the SARS-like disease, and strategies for combating this newly emerged infectious disease should be prepared. It is believed that the existing SARS research may provide a useful template for developing vaccines and therapeutics against HCoV-EMC infection, but so far, no effective anti-SARS vaccines and therapeutics have been well developed.
SARS, which is caused by the SARS coronavirus (SARS-CoV), emerged from China and caused nearly 8500 cases and 916 deaths during the outbreak in 2002 and 2003 [3–5]. Although SARS is currently under control, the possibility of a new SARS outbreak remains a global concern because of the potential for zoonotic transmission of SARS-CoV or SARS-CoV-like viruses from their natural hosts to humans, or the accidental or intentional release of laboratory SARS-CoV strains. Therefore, developing vaccines and therapeutics for the prevention and treatment of SARS is still a matter of urgency.
During the global 2002/2003 SARS pandemic, many foundations, pharmaceutical companies and governments provided abundant funds to support the development of anti-SARS vaccines and therapeutics. However, after the disappearance of SARS, these funds were either withdrawn or discontinued because of the lack of a sustainable market of the products to be developed.
A number of inactivated and live-attenuated SARS vaccines, as well as those based on vectors encoding the full-length S protein of SARS-CoV, showed high immunogenicity in inducing neutralizing antibody responses and protection against SARS-CoV challenge. However, most of these vaccine candidates may also induce immunopathology or other harmful immune responses, raising concerns about their safety. On the other hand, recombinant proteins containing the receptor-binding domain of the SARS-CoV S protein could be developed as a safe and effective SARS vaccine. This potential is based on the ability of receptor binding domain-based vaccine to induce stronger cross-neutralizing antibody responses and protection against SARS-CoV, with a correspondingly lower probability of inducing immunopathology, in contrast with the other SARS vaccine candidates mentioned previously.
So far, no specific anti-SARS drugs have been developed. A number of drug candidates, including the SARS-CoV fusion inhibitors, proteinase (e.g., 3C-like cysteine proteinase) inhibitors, PLpro inhibitors, RNA-dependent RNA polymerase inhibitors, helicase inhibitors, siRNAs inhibiting SARS-CoV structural proteins E, M and N, and therapeutic antibodies, have been developed in laboratory and preclinical studies. However, none of them have been forwarded to clinical trials, possibly for the same reasons as previously described for vaccine development.
Apart from financial support, another main challenge for the clinical development of anti-SARS vaccines is the lack of endemic SARS and the lethal nature of the disease. It is not ethical to conduct human efficacy studies by exposing healthy human volunteers to a lethal agent like SARS-CoV. Fortunately, however, according to the ‘Animal Rule’, a pivotal animal efficacy study can be conducted for evaluating the in vivo efficacy of the anti-SARS vaccines using two animal species that exhibit pathophysiology of the disease and host immune responses that closely match those of humans. The data from these animal experiments can then be considered by the US FDA as evidence of effectiveness of the tested vaccine.
In 2003, the Chinese population was infected with a virus causing Severe Acute Respiratory Syndrome (SARS) in Guangdong province. The virus was confirmed as a member of the Beta-coronavirus subgroup and was named SARS-CoV,. The infected patients exhibited pneumonia symptoms with a diffused alveolar injury which lead to acute respiratory distress syndrome (ARDS). SARS initially emerged in Guangdong, China and then spread rapidly around the globe with more than 8000 infected persons and 776 deceases. A decade later in 2012, a couple of Saudi Arabian nationals were diagnosed to be infected with another coronavirus. The detected virus was confirmed as a member of coronaviruses and named as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The World health organization reported that MERS-coronavirus infected more than 2428 individuals and 838 deaths. MERS-CoV is a member beta-coronavirus subgroup and phylogenetically diverse from other human-CoV. The infection of MERS-CoV initiates from a mild upper respiratory injury while progression leads to severe respiratory disease. Similar to SARS-coronavirus, patients infected with MERS-coronavirus suffer pneumonia, followed by ARDS and renal failure.
Recently, by the end of 2019, WHO was informed by the Chinese government about several cases of pneumonia with unfamiliar etiology. The outbreak was initiated from the Hunan seafood market in Wuhan city of China and rapidly infected more than 50 peoples. The live animals are frequently sold at the Hunan seafood market such as bats, frogs, snakes, birds, marmots and rabbits. On 12 January 2020, the National Health Commission of China released further details about the epidemic, suggested viral pneumonia. From the sequence-based analysis of isolates from the patients, the virus was identified as a novel coronavirus. Moreover, the genetic sequence was also provided for the diagnosis of viral infection. Initially, it was suggested that the patients infected with Wuhan coronavirus induced pneumonia in China may have visited the seafood market where live animals were sold or may have used infected animals or birds as a source of food. However, further investigations revealed that some individuals contracted the infection even with no record of visiting the seafood market. These observations indicated a human to the human spreading capability of this virus, which was subsequently reported in more than 100 countries in the world. The human to the human spreading of the virus occurs due to close contact with an infected person, exposed to coughing, sneezing, respiratory droplets or aerosols. These aerosols can penetrate the human body (lungs) via inhalation through the nose or mouth (Fig. 2),,,.
The percentages of asymptomatic cases [36.72% (47/128) vs 17.39% (16/92), p = 0.001] and mild cases [43.75% (56/128) vs 18.48% (17/92), p <0.001] in HCP were much higher than those in non-HCP. However, the percentage of severe MERS cases in HCP was significantly lower than that in non-HCP [12.5% (16/128) vs 27.17% (25/92), p = 0.006)]. Similarly, CFR of MERS-HCP was statistically lower than that in MERS-non-HCP [(7.0% (9/128) vs 36.96% (34/92), p<0.001] Table 2. By contrast, severe SARS cases were more common in HCP than in non-HCP [86.76% (86/98) vs 75.50% (188/249), p = 0.012]. Nonetheless, CFR of SARS in HCP was significantly lower than that in non-HCP [12.24% (12/98) vs.24.50% (61/249), p = 0.012, Table 2]. In general, MERS-HCP were predominantly associated with mild cases whereas SARS-HCP were more likely to develop severe cases. On the other hand, MERS-non-HCP cases had higher CFR than SARS-non-HCP cases [36.96% (34/92) vs 24.50% (61/249), p = 0.023, Table 2.
The mean age in worldwide total 174 MERS cases was 49 years (range: 2~90 years), of which 143 MERS-HCP cases were aged 40 years (range: 24~74 years), significantly younger than in 31 MERS-non-HCP cases [47.5 years (range: 2~90 years), p = 0.035]. Similarly, the mean age in 347 total Taiwan SARS cases was 42 years (range: 0~94), of which the mean age in 98 SARS-HCP cases was 35 years (range: 21~68 years), also much younger than that of SARS-non-HCP [45 years (range: 0~94 years), p = 0.044]. Noticeably, the mean ages of MERS-HCP and total MERS cases were significantly older than those for SARS-HCP (p = 0.006) and total SARS cases in Taiwan (p = 0.0002). (Fig 3A and 3B and Table 1). We stratified the age groups between the MERS-HCP and SARS-HCP cases; the results show that there are no signature differences in the mean age of the 20~, 30~, 40~, 50~, 60–70 groups between the two groups.
In terms of sex distribution, among MERS cases whose gender information was available, 65% of 1359 total MERS cases were male, of which 54.46% of 101 MERS-HCP and 69.55% of 1258 MERS-non-HCP [p = 0.002] were male respectively. However, in Taiwan females were dominant in the 98 SARS-HCP cases (82.65%, 81/98) and 249 SARS-non-HCP cases (55.0%, 137/249) [p = 0.027], while males accounted for 46.93% (3778/8050) of total global SARS cases. (Fig 3A and 3B and Table 1). We stratified the gender groups between the MERS-HCP and SARS-HCP cases, with the results showing significant differences in the gender distribution of the 20~, 30~, 40~, 50~, 60–70 groups between the two groups.
Regarding the working departments of HCP, 58.82% (10/17) of MERS-HCP cases worked in an intensive care unit (ICU), while 17.65% (3/17), 11.76% (2/17), and 11.76% (2/17) worked in Emergency rooms (ER), internal medicine and other departments in hospitals, respectively. Among the 57 of 98 SARS-HCP cases with their information of working departments available, ER (31.58%, 18/57), wards of internal medicine (26.31%, 15/57), and ICU (10.53%, 6/57) and other wards (31.58%, 18/57) were the four major working sites (Table 1). Our statistics for department will be heavily biased because of the missing department information in the HCP infections with MERS and SARS-CoV.
Among total 169 hospital-acquired MERS cases, patients accounted for 46.2%, family members or visitors 34.9%, and HCP (19.0%). Among the 227 laboratory-confirmed SARS cases from hospital infections, HCP accounted the highest (43.2%), followed by patients (28.6%), family members or visitors (19.8%), foreign caregivers (4.4%), and others (4.0%). Nurses were the major populations in both groups (Fig 4A and 4B).
The severe acute respiratory syndrome (SARS) is a febrile respiratory illness primarily transmitted by respiratory droplets or close personal contact. A global outbreak of SARS between March 2003 and July 2003 caused over 8,000 probable or confirmed cases and 774 deaths. The causative organism has been identified as a novel coronavirus (SARS-CoV) [2–4]. The overall mortality during the outbreak was estimated at 9.6%. The overriding clinical feature of SARS is the rapidity with which many patients develop symptoms of acute respiratory distress syndrome (ARDS). This complication occurred in approximately 16% of all patients with SARS, and when it occurred was associated with a mortality rate of 50%.
At the time of the SARS epidemic it was not known what treatments would reduce SARS-related illness and deaths. Because the urgency of the international outbreak did not allow time for efficacy studies, physicians in Canada and Hong Kong treated the earliest patients with intravenous ribavirin, based on its broad-spectrum antiviral activity. Corticosteroids and immune-modulating agents were often prescribed empirically. Soon after SARS-CoV was identified as the causative agent, antiviral screening programs were initiated; these programs reported several antiviral agents that inhibited SARS-CoV replication in vitro. These results led to the experimental use of protease inhibitors and interferon alpha (IFN-α) in the treatment of patients.
The most commonly used treatments for SARS are associated with adverse effects when used for other conditions (Table S1). In October 2003, the WHO established an International SARS Treatment Study Group, consisting of experts experienced in managing SARS. The group recommended a systematic review of potential treatment options to identify the targets for proper evaluation in trials should the disease recur. This paper reports on this systematic review designed to summarise available evidence on the effects of ribavirin, lopinavir and ritonavir (LPV/r), corticosteroids, type I IFN, intravenous immunoglobulin (IVIG), or convalescent plasma in relation to (1) SARS-CoV replication inhibition in vitro; (2) mortality or morbidity in SARS patients; and (3) effects on ARDS in adult patients.
SARS first emerged in late 2002 in Guangdong Province, southern China, as a novel clinical severe disease (termed “atypical pneumonia”) marked by fever, headache and subsequent onset of respiratory symptoms including cough, dyspnea and pneumonia. Being highly transmissible among humans, SARS rapidly spread to Hong Kong and other provinces across China and then to other 28 countries [6, 7]. By July 2003, it had caused 8096 confirmed cases of infection in 29 countries, 774 (9.6 %) of which were fatal (http://www.who.int/csr/sars/country/table2004_04_21/en/). The second outbreak in 2004 only caused 4 infections with no mortality nor further transmission.
The MERS epidemic emerged in the Kingdom of Saudi Arabia (KSA) since June 2012, with a similar clinical syndrome to SARS but seemingly less transmissible. In addition to respiratory illness, renal failure was identified in some severe cases [9–11]. Unlike SARS which had numerous super-spreader events, most MERS cases were independent clusters and limited to countries in the Middle East, particularly in KSA. Limited MERS cases have been reported in African and European countries and the United States of America, but exclusively in individuals travelling back from the Middle East. Some patients were reported to have a history of contact with camels while many other cases lacked this epidemiological link [9–11]. The MERS pandemic in the Republic of Korea in 2015 was caused by a single person who returned from travel in the Middle East. This made the Republic of Korea to be home to the second largest MERS epidemic with a total of 185 confirmed cases and 36 deaths [11, 12]. By 18 August 2015 a total of 1413 laboratory-confirmed cases of MERS have been reported worldwide with a median age of 50 years, including 502 related deaths. The mortality of MERS (approximately 35 %) is much higher than that of SARS (around 10 %).
Coronaviruses belong to the Coronaviridae family in the Nidovirales order. Corona represents crown-like spikes on the outer surface of the virus; thus, it was named as a coronavirus. Coronaviruses are minute in size (65–125 nm in diameter) and contain a single-stranded RNA as a nucleic material, size ranging from 26 to 32kbs in length (Fig. 1). The subgroups of coronaviruses family are alpha (α), beta (β), gamma (γ) and delta (δ) coronavirus. The severe acute respiratory syndrome coronavirus (SARS-CoV), H5N1 influenza A, H1N1 2009 and Middle East respiratory syndrome coronavirus (MERS-CoV) cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) which leads to pulmonary failure and result in fatality. These viruses were thought to infect only animals until the world witnessed a severe acute respiratory syndrome (SARS) outbreak caused by SARS-CoV, 2002 in Guangdong, China. Only a decade later, another pathogenic coronavirus, known as Middle East respiratory syndrome coronavirus (MERS-CoV) caused an endemic in Middle Eastern countries.
Recently at the end of 2019, Wuhan an emerging business hub of China experienced an outbreak of a novel coronavirus that killed more than eighteen hundred and infected over seventy thousand individuals within the first fifty days of the epidemic. This virus was reported to be a member of the β group of coronaviruses. The novel virus was named as Wuhan coronavirus or 2019 novel coronavirus (2019-nCov) by the Chinese researchers. The International Committee on Taxonomy of Viruses (ICTV) named the virus as SARS-CoV-2 and the disease as COVID-19,,. In the history, SRAS-CoV (2003) infected 8098 individuals with mortality rate of 9%, across 26 contries in the world, on the other hand, novel corona virus (2019) infected 120,000 induviduals with mortality rate of 2.9%, across 109 countries, till date of this writing. It shows that the transmission rate of SARS-CoV-2 is higher than SRAS-CoV and the reason could be genetic recombination event at S protein in the RBD region of SARS-CoV-2 may have enhanced its transmission ability. In this review article, we discuss the origination of human coronaviruses briefly. We further discuss the associated infectiousness and biological features of SARS and MERS with a special focus on COVID-19.
We prepared a protocol that defined our scope, inclusion criteria, and outcomes to be assessed. The interventions we included were defined by the WHO: ribavirin, LPV/r, corticosteroids, type I IFN, convalescent plasma, or IVIG.
The types of study we included were: (1) in vitro studies, in which the authors examined inhibition of SARS-CoV viral replication, and data from an assay in human or animal cell line; (2) in vivo studies, which included randomised controlled trial (RCT), or prospective uncontrolled study design, or retrospective cohort design, or case-control design, or a case series, and patients treated for SARS, and ten or more patients; and (3) studies of ARDS that included RCT, or systematic review, and treatment for ARDS or acute lung injury, and 20 or more patients. In February 2005, we systematically searched the literature databases MEDLINE, EMBASE, BIOSIS, and the Cochrane Central Register of Controlled Trials (CENTRAL) for articles that included the selected treatments (Table S2).
The full text of each identified study was retrieved and each was independently reviewed by two authors (LS and RB). Publications in Chinese were selected after review of the English abstract. Unpublished data were not sought, as the task of summarising existing published data was extensive and the International SARS Treatment Group indicated that much of the clinical data had already been published. We used the QUOROM checklist to help ensure the quality of this review (Table S3).
Data from the full text of studies in English were extracted independently by two authors (LS and RB). Data from the Chinese literature were extracted with the assistance of a translator. Because the Chinese articles were reviewed by only one author, the consistency of the translated information with that from English articles was maintained by subsequent discussion with the translator to verify the extracted data.
We established explicit criteria to assess the level of evidence for each human treatment study (Box 1). Since the treatments chosen for evaluation were often given in combination, evidence was classified by the treatment that was given to all patients in the cohort or given to some with the author's intention of studying its effects. If putative effects within a study included several drugs, then we extracted data for each intervention. The level of evidence was independently classified by two authors (LS and RB). Chinese studies were appraised and classified in the same way using translated information extracted from each report. Discrepancies were resolved by consensus.
SARS, also known as “atypical pneumonia”, was the first well documented HCoV-caused pandemic in human history and the etiological agent is SARS-CoV, the third HCoV discovered 14,15. The first case of SARS can be traced back to late 2002 in Guangdong Province of China. The SARS epidemic resulted in 8,096 reported cases with 774 deaths, spreading across many countries and continents. Apart from the super-spreaders, it was estimated that each case could give rise to approximately two secondary cases, with an incubation period of 4 to 7 days and the peak of viral load appearing on the 10th day of illness 14,15.
Patients infected with SARS-CoV initially present with myalgia, headache, fever, malaise and chills, followed by dyspnea, cough and respiratory distress as late symptoms 14,15. Lymphopenia, deranged liver function tests, and elevated creatine kinase are common laboratory abnormalities of SARS 14,15. Diffuse alveolar damage, epithelial cell proliferation and an increase of macrophages are also observed in SARS patients 31. Approximately 20-30% of patients subsequently require intensive care and mechanical ventilation. In addition to lower respiratory tract, multiple organs including gastrointestinal tract, liver and kidney can also be infected in these severe cases, usually accompanied with a cytokine storm, which might be lethal particularly in immunocompromised patients. The virus was first isolated from the open lung biopsy of a relative of the index patient who travelled to Hong Kong from Guangzhou 14,15. Since then, tremendous efforts have been dedicated to HCoV research.
As a novel disease, COVID-19 has just started to manifest its full clinical course throughout thousands of patients. In most cases, patients can recover gradually without sequelae. However, similar to SARS and MERS, COVID-19 is also associated with high morbidity and mortality in patients with severe cases. Therefore, building a prognosis model for the disease is essential for health-care agencies to prioritize their services, especially in resource-constrained areas. Based on clinical studies reported thus far, the following factors may affect or be associated with the prognosis of COVID-19 patients (Table 3):Age: Age was the most important factor for the prognosis of SARS 99, which is also true for COVID-19. COVID-19 mainly happened at the age of 30-65 with 47.7% of those patients being over 50 in a study of 8,866 cases as described above 37. Patients who required intensive care were more likely to have underlying comorbidities and complications and were significantly older than those who did not (at the median age of 66 versus 51) 34, suggesting age as a prognostic factor for the outcome of COVID-19 patients.Sex: SARS-CoV-2 has infected more men than women (0.31/100,000 versus 0.27/100,000), as described above 37.Comorbidities and complications: Patients with COVID-19 who require intensive care are more likely to suffer from acute cardiac injury and arrhythmia 34. Cardiac events were also the main reason for death in SARS patients 55,65,99. It has been reported that SARS-CoV-2 can also bind to ACE2-positive cholangiocytes, which might lead to liver dysfunctions in COVID-19 patients 100. It is worth noting that age and underlying disease are strongly correlated and might interfere with each other 55.Abnormal laboratory findings: The C-reactive protein (CRP) level in blood reflects the severity of inflammation or tissue injury and has been proposed to be a potential prognostic factor for disease, response to therapy, and ultimate recovery 101. The correlation of CRP level to the severity and prognosis of COVID-19 has also been proposed 101. In addition, elevated lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) may also help predict the outcome. These enzymes are expressed extensively in multiple organs, especially in the heart and liver, and are released during tissue damage 102,103. Thus, they are traditional markers for heart or liver dysfunctions.Major clinical symptoms: Chest radiography and temporal progression of clinical symptoms should be considered together with the other issues for the prediction of outcomes and complications of COVID-19.Use of steroids: As described above, steroids are immunosuppressant commonly used as an adjunctive therapy for infectious diseases to reduce the severity of inflammatory damage 104. Since a high dosage of corticosteroids was widely used in severe SARS patients, many survivors suffered from avascular osteonecrosis with life-long disability and poor life quality 105. Thus, if needed, steroids should be used at low dosage and for a short time in COVID-19 patients.Mental stress: As described above, during the COVID-19 outbreak many patients have suffered from extraordinary stress as they often endured long periods of quarantine and extreme uncertainty and witnessed the death of close family members and fellow patients. It is imperative to provide psychological counseling and long-term support to help these patients recover from the stress and return to normal life 66.
Prior to the outbreaks of SARS and MERS, the clinical importance and epidemic possibility of CoVs had been recognized by researchers, (Table 1). In 2002, a SARS epidemic that originated in Guangdong Province in China resulted in 916 deaths among more than 8098 patients in 29 countries, identifying SARS as the first new infectious disease of the 21st century. Ten years later, the World Health Organization (WHO) published 2254 laboratory-confirmed cases of MERS-CoV that occurred from 2012 to 16 September 2018, with at least 800 deaths in 27 countries. Remarkably, more than 80% of recent research into the virology and genetics of this infection indicated that bats could be the possible natural reservoirs of both SARS and MERS-CoV. Palm civets and dromedary camels are also possible intermediary hosts of SARS and MERS, respectively, before dissemination to humans.
The transmission mechanism of SARS-CoV and MERS-CoV has yet to be fully understood. For transmission from animals to humans, direct contact with the intermediary host might be one route. Recent reports demonstrated that camel workers in Saudi Arabia with high prevalence of MERS-CoV infection may contribute to the transmission of MERS. Some customs and habits may also be conducive to transmission, such as the consumption of milk, urine, or uncooked meat. In this way, MERS-CoV was transmitted from dromedary camels directly to humans, principally in the Arabian Peninsula, and this is considered to be the main route of transmission from animals to humans, causing significant morbidity and mortality. Human-to-human spread has also been detected, especially through nosocomial transmission. Delays in diagnosis in hospitals might lead to secondary cases among healthcare workers, family members, or other patients sharing rooms. Among the reported cases of SARS, 22% were healthcare workers in China and more than 40% were healthcare workers in Canada. Nosocomial transmission for MERS has similarly been seen in the Middle East and in the Republic of Korea. Outbreaks in other countries all resulted from the reported cases in the Middle East or North Africa, and transmission was the result of international travel. Both SARS and MERS caused large outbreaks with significant public health and economic consequences.
Avian infectious bronchitis virus was the first CoV isolated in 1930. Different CoVs were subsequently isolated in infected rodents and domestic animals, including mouse, pig, cow, turkey, cats, and dogs. CoVs were once believed not to cause human disease, but this was changed after the successful isolation of HCoV strain B814 from the clinical specimen of patients with common cold by serial passage of inoculum in tracheal organ culture in 1962. In the 1960s, several novel HCoVs were described but no further characterization was performed in most cases. 229E and OC43 were known as causative agents of the common cold and upper respiratory tract infection, accounting for up to 30% of cases with common cold. 229E is a prototype strain isolated using tracheal organ culture. OC43 was isolated from organ culture and subsequent serial passage in the brain of suckling mice. The clinical features of 229E and OC43 infection were characterized in human volunteer study. In most cases, natural infection with HCoVs results in mild common cold-like symptoms. Severe lower respiratory tract infection develops only in immunocompromised patients. Apart from a respiratory infection, 229E and OC43 were suspected to infect the central nervous system (CNS) as mRNA and CoV-like particles were detected in CNS samples of patients with multiple sclerosis. This claim was further supported by the susceptibility of human neural primary culture to 229E and OC43. However, the influence of 229E and OC43 on the development and progression of multiple sclerosis awaits further investigations.
In the pre-SARS era, it was generally accepted that HCoVs cause mild respiratory disease only. This concept was changed after the emergence of SARS-CoV. The first reported case of SARS-CoV infection was retrospectively dated back to November 2002 in Guangdong Province of China. In the subsequent seven months, the SARS epidemic resulted in over 8000 reported cases in 37 countries with a case fatality of 9.6%. The superspreading events in SARS-CoV transmission caused fears in the society. Although the exact cause of superspreading remains to be understood, the host but not the virus only is thought to play a key role in the release of large amounts of virions in superspreading. In this regard, the use of immunosuppressive agents such as high-dose steroid in an early phase of viral infection as a treatment modality might boost viral replication leading to the shedding of large amounts of virus. Likewise, the immunocompromised status of the superspreader could have the same effect. In addition, mutation of virus susceptibility genes encoding restriction factors implicated in host antiviral defence would also result in the shedding of extraordinarily large quantities of the virus. In other words, compromising host antiviral defence or decoupling host antiviral immune response from viral replication might allow or facilitate superspreading.
SARS-CoV was isolated and identified as the causative agent of SARS. Unlike 229E and OC43, SARS-CoV infection causes lower respiratory tract infection, accompanied by a cytokine storm in patients with poor outcome. Life-threatening ARDS was developed in some critically ill patients. Apart from a respiratory infection, gastrointestinal and CNS infection was also found in some patients with SARS. FRHK4 and Vero-E6 cells played an important role in the discovery of SARS-CoV. The same as chicken embryos in which other CoVs including avian infectious bronchitis virus were isolated and cultured, these cells are highly susceptible to SARS-CoV infection because they are type I interferon-defective. Consistent with this, infection of STAT1−/− mice with SARS-CoV resulted in a lethal outcome with a profibrotic phenotype in the lung. These mice cannot clear the virus. All these highlight the importance of host antiviral response in the control of SARS-CoV infection at the cellular and organismal level.
In the post-SARS era, CoV research was brought back to the limelight and more effort was put into the search for novel HCoVs. The search was fruitful and two new HCoVs were identified in human samples positive for HCoV but not for SARS-CoV. NL63 and HKU1 were first isolated from a child suffering from bronchiolitis and a patient with pneumonia, respectively. HKU1 is difficult to culture and can only be propagated in primary human airway epithelial cells cultured at the air–liquid interface. Similar to 229E and OC43, NL63 and HKU1 were found worldwide, causing mild respiratory diseases. Particularly, NL63 infection was associated with virus-induced croup in children. All these four viruses are community-acquired HCoVs that are well adapted to humans. Only in rare cases, they might be accidentally mutated to cause more severe lower respiratory tract disease. For example, a subtype of NL63 was recently found to be associated with severe lower respiratory tract infection in China.
Another highly pathogenic HCoV outbreak emerged in 2012 from Saudi Arabia. A new HCoV subsequently named MERS-CoV was isolated from patients who developed acute pneumonia and renal failure. Exported MERS cases were also reported outside Arabian Peninsula occasionally. One relatively big secondary outbreak with 186 confirmed cases occurred in South Korea in 2015. Up to January 2020, >2500 laboratory-confirmed case were reported with a case fatality of 34.4%. Clinical symptoms were diverse in MERS patients, ranging from asymptomatic to ARDS. Acute renal injury was unique in MERS patients, but it is more commonly observed in the Middle East than in South Korea. MERS-CoV replicates well in many different types of cells and extrapulmonary tissues including the kidney and intestinal tract. MERS-CoV is endemic in Arabian Peninsula with sporadic, but recurrent outbreaks occurring continuously since 2012.
The first HCoV-229E strain was isolated from the respiratory tract of patients with upper respiratory tract infection in the year of 1966 27, and was subsequently adapted to grow in WI-38 lung cell lines 28. Patients infected with HCoV-229E presented with common cold symptoms, including headache, sneezing, malaise and sore-throat, with fever and cough seen in 10~20% cases 29. Later in 1967, HCoV-OC43 was isolated from organ culture and subsequent serial passage in brains of suckling mice 28. The clinical features of HCoV-OC43 infection appear to be similar to those caused by HCoV-229E, which are symptomatically indistinguishable from infection with other respiratory tract pathogens such as influenza A viruses and rhinoviruses 28.
Both HCoV-229E and HCoV-OC43 are distributed globally, and they tend to be predominantly transmitted during the season of winter in temperate climate 2. Generally, the incubation time of these two viruses is less than one week, followed by an approximately 2-week illness 28. According to a human volunteer study, healthy individuals infected with HCoV-229E developed mild common cold 30. Only a few immunocompromised patients exhibited severe lower respiratory tract infection.
According to demographic studies so far, COVID-19 seems to have different epidemiological features from SARS. In addition to replicating in the lower respiratory tract, SARS-CoV-2 can efficiently replicate in the upper respiratory tract and causes mild or no symptoms in the early phase of infection, similar to other CoVs that cause common colds 106. Therefore, infected patients at the early phase or incubation period can produce a large amount of virus during daily activities, causing great difficulty for the control of the epidemic. However, the transmission of SARS-CoV was considered to occur when the patients are severely ill, while most transmission did not happen at the early phase 107. Thus, the current outbreak of COVID-19 is much more severe and difficult to control than the outbreak of SARS.
Great efforts are currently underway in China including the lockdown of Wuhan and surrounding cities and continuous quarantine of almost the entire population in hopes of interrupting the transmission of SARS-CoV-2. Although these actions have been dramatically damaging the economy and other sectors of the country, the number of new patients is declining, indicating the slowdown of the epidemic. The most optimistic estimate is that the outbreak will end by March and the downswing phase will last for 3-4 months 108. However, some other experts are not that optimistic. Paul Hunter, et al., estimated that COVID-19, which seems substantially more infectious than SARS, will not end in 2020 109. Ira Longini, et al., established a model to predict the outcome of the epidemic and suggested that SARS-CoV-2 could infect two-thirds of the global population 110.
A Canadian group reported that SARS-CoV-2 was detected in both mid-turbinate and throat swabs of patients who recovered and left the hospital 2 weeks earlier 111, which indicates that the newly identified virus could become a cyclical episode similar to influenza. However, promising signs have occurred in China based on the declining number of new cases, indicating the current strategies might have been working. Ebola was originally predicted to cause up to a million cases with half a million deaths. However, via strict quarantine and isolation, the disease has eventually been put under control 112,113. It is possible, similar to SARS-CoV, that SARS-CoV-2 might become weaker in infectivity and eventually die down or become a less pathogenic virus co-existent with humans. A comparison of the epidemic of COVID-19 with that of SARS and MERS is provided below (Fig. 5).
Patient clinical details were obtained through review of health records which was conducted for a study of clinical presentation and management of SARS. The study was approved by the IRB of each hospital where patients were treated. Individual consents were not obtained which is the practice for chart review studies in which individual patient identifying information is not required. All patients in the SARS outbreak were given a unique identifying number and all data were coded with this unique number. There was no information collected that could identify the patient personally.
HCWs blood samples were obtained through a seroprevalence study, which was part of the public health investigation and received IRB approval at each hospital where HCWs were enrolled. HCWs provided consent for blood samples.
Approvals for both studies were obtained from The Mount Sinai Hospital Research Ethics Board as well as the Research Ethics Boards/Committees of the following institutions: Sunnybrook Health Center. North York General Hospital, The Scarborough Hospital, Rouge Valley Health Care, Humber River Regional Hospital, Markham Stuffily Hospital, St. Michael's Hospital, St. Joseph's Health Center, Southlake Regional Health Center, Toronto East General Hospital, University Health Center, and Lakeridge Health Center.
HCWs were interviewed as part of a public health investigation into the transmission of SARS-CoV. HCWs were invited to participate and consent was implied by willingness of HCWs to be interviewed about their experiences. No IRB approval was required as these interviews occurred as part of the public health outbreak investigation which is a legislated responsibility of the Ontario public health units.
Both SARS-CoV and MERS-CoV are emerging zoonotic pathogens that crossed the species barriers to infect humans [10, 53, 99]. Evidence showed that SARS-CoV and MERS-CoV originated from bats, the nature reservoirs, then transmitted to human via intermediate hosts civets and camels, respectively [10, 40, 53, 81, 100]. Human SARS-CoV infection originated from the direct contact between humans and civets in markets or restaurants. Closing wet markets and cleaning civet cut off the spread chain of SARS-CoV and effectively ended the SARS epidemic [40, 42, 101]. In contrast, MERS-CoV is believed to have existed in camels for a very long time and camels are widely distributed in Middle East and African countries, serving as important transport vectors and sources of meat and milk for the local population. Therefore, it is difficult to adopt the same strategy of SARS-CoV control in the prevention of future MERS-CoV outbreaks. Until a comprehensive approach is found, which most likely will involve the effective vaccination of camels against MERS-CoV among other measures, it is envisaged that sporadic human infection will persist for some time in the future [11, 70].
Humans have been exposed continually to newly emerged infectious diseases-, especially 1918 influenza, 2003 severe acute respiratory syndrome (SARS), 2009 H1N1 influenza, 2012 novel coronavirus, 2013 H7N9 influenza pandemics and Ebola virus in 2014. Without exception, these viruses were harbored in an animal reservoir and jumped the species barrier to infect humans, presenting a serious threat to human health. SARS, “the Black Death in the 21st century”, spread to 32 countries and regions worldwide within a few months. Globally, there were 8096 cases of SARS and 774 deaths, with 5327 cases in Mainland China, involved 29 provinces, resulted in 349 deaths, and caused total economic losses of $18.3 billion, which accounted for 1.3% of the gross domestic product in Mainland China.
There have been many studies on virus transmission during the SARS epidemic, which have included three main aspects. (1) Use of the Susceptible–Infected, Susceptible–Infected–Removed or Susceptible–Exposed–Infectious–Recovered model of infectious diseases-. For example, Li et al. introduced the SI model and piecewise SI model to forecast the cumulative number of cases of SARS in Beijing. The piecewise SI model showed the change point on April 21, 2003. Wang et al. used the SIR or SEIR model to study SARS transmission in Beijing, Hong Kong or Singapore. Their results showed that public health interventions such as early recognition, prompt isolation, and appropriate precautionary measures, could effectively limit spread of the virus. (2) Use of spatial statistics to explore the spatial clustering characteristics of SARS-. For example, some researchers used geostatistic, such as semivariogram, Moran’s I and LISA statistics to study the risks of SARS transmission and spatiotemporal evolution in Beijing or Guangzhou. This provided a scientific basis for the emergency plan for the outbreak of SARS or other unexpected new epidemics in urban areas. (3) Use of dots diffusion model to study spread of the SARS epidemic by different modes of transport, and use flying spot spread model to study input–output sources of the spread of SARS in different regions,, to predict trends in the spread of SARS in the medium to long term on a national and metropolitan basis. Many studies have explored the transmission of the SARS epidemic from the affected to neighboring areas-,-, such as neighborhoods, hospitals, and other cities. These studies were good at reflecting the spatial diffusion of SARS in the local area, but not at an interprovincial level.
Information on the SARS in-out flow transmission at provincial level in Mainland China helps us to understand the temporospatial spread of infectious diseases like SARS. This provides a good reference for prevention of similar infectious disease outbreaks in the future. To reflect the interprovincial diffusion paths and characteristics of the SARS epidemic, the present study used in-out flow data at provincial and municipal level to study the spatial spread of the SARS epidemic in Mainland China. Instead of single spatial location studies in the current most population epidemiological literature, we used in-out flow model to explore the interregional transmission of the disease. This can better explain the spatiotemporal evolution in the process of disease transmission in the country.
From Eqn. 5 we define fresh fear at day i. We parameterize as(10)
Here is a variable (the daily reported SARS cases), and L is a fixed parameter, representing the loss of underground ridership for each reported SARS case. L is empirically determined by comparing model results with the actual underground daily ridership in 2003.
From Eqn. 4, it can be determined that when(11)
This indicates that instantaneous passenger loss (fresh fear ) on day dissipates exponentially to the following days with an -folding time of days. Here the e-folding time measures the dissipation of the fresh factor () due to each new reported SARS cases (residual fear, ), reflecting the public expectation of the risk of contacting the SARS virus arises from each newly reported SARS cases. In this work we also empirically determined k by comparing model results with daily underground ridership in 2003. In a similar way to atmospheric chemistry, we can call as the lifetime for the fresh fear or the resident time of the fresh fear in the mind of the people.
We note that previous work has shown that effects of respectively epidemic mortality and morbidity on social phenomena can be different. In this work we haven't included the number of deaths in the model. The first death occurred on 26 April (Julian Day 116), which is within the period (22 April, Julian Day 112 - 1 May, Julian Day 121) when the probable cases more than tripled, from 28 to 89. The source of these outbreaks was due to transmissions occurred in the Taipei City Hoping Hospital. To what extent mortality has an (in)dependent effect on riderships or to what extent morbidity has an independent effect above and beyond mortality remains to be explored.
We also note that, as the model for this work does not consider the effect of the lethality, the model assumes that any news about the increasing or decreasing lethality and cases/deaths from other countries does not affect fear and ridership in Taipei. It remains to be explored in the model the effect of the weekly global number of new cases, deaths, and information on the possible change of lethality over time in addition to the data on Taiwan and Taipei.
Formal ethical approval was not required for the study because all patient-identifiable fields were removed and the statistical analysis on the population was applied.
The SARS data from November 2002 to May 2003 in Mainland China were provided by the Chinese Center for Disease Control and Prevention. There were a total of 5327 cases of SARS (Figure 1), with each person a record in the dataset. The attribute items in the dataset included sex, age, occupation, registered residence, workplace or current residence, onset location, reporting units, onset time, hospitalization time, diagnosis time, and other information, which was separate information collected from the SARS case. Registered residence refers to the “hukou” address, is the address of a person’s ID card, and reflects the origin of the floating population. Permanent residence refers to living in a place for more than six months. Current residence is almost consistent with permanent residence, but easier to change than permanent residence. Workplace refers to the location of a person’s job. Onset location refers to the approximate place of SARS onset. Medical location refers to the location of treatment SARS, and the medical unit is an officially designated hospital.
SARS in-out flow occurred between permanent residence, onset location and medical location. According to the definition of in-out flow, transmission of SARS cases in Mainland China was divided into internal flow and external flow. External flow was further divided into self-spreading, hospitalized, and migrant flows. They could be interpreted by epidemiology (Additional file 1: Table S1). Permanent residence is based on current residence, but if there is no current residence, workplace is used instead; onset location is based on place of SARS onset; and medical location is based on the reporting location.
SARS data processing followed three steps. (1) Extraction of valid records. We only used three places (permanent residence, onset location and medical location) with complete spatial location information, that is, if one of these pieces of information was missing, the record was removed. (2) Determining the three types of spatial location information at the provincial or municipal level. (3) Selecting data with the three spatial locations within the same province/municipality as internal flow (also called provincial flow), or data with the different provinces/municipalities as external flow (also called interprovincial flow). The external flow was subdivided into self-spreading flow, hospitalized flow and migrant flow. Self-spreading flow represented a typical external flow, with spatial displacement of SARS cases only within the province or municipality of onset and medical locations. Hospitalized flow indicated a typical kind of external flow, with spatial displacement of SARS cases that had been seen by a hospital doctor. Migrant flow was a typical kind of external flow with spatial displacement of SARS cases among migrant workers, and got sick but had to be treated in their hometown. The flow was not only applicable to patients who were rural migrant workers, but also included a small number of people with other occupations. For example, 41.5% of migrant flow was related to migrant workers (people seek work to earn money in the non-harvest season, and the salary is their main income for the year), 1.2% of migrant flow was related to workers (individuals without production materials, rely on the pay by being employed in manual or technical work), and 3.7% of migrant flow was related to public staff. Take Beijing as permanent residence for example, if people are in the permanent population in Beijing, and their onset and medical location locations are also in Beijing, they belong to provincial flow. If people are non-permanent population in Beijing, but their onset and medical location locations are in Beijing, they belong to self-spreading flow. If people are non-permanent population in Beijing, and their onset location is also not in Beijing, but their medical location is in Beijing, they belong to hospitalized flow. If people are in the permanent population in Beijing, their onset location is not in Beijing, but their medical location is still in Beijing, they belong to migrant flow. Following the above three steps of data processing, and elimination of invalid records (Additional file 3: Table S3), we finally obtained 1776 cases of SARS internal flow, which accounted for 90% of SARS in-out flow data; and 198 cases of SARS external flow, accounting for 10% of in-out flow data, including 101 cases of self-spreading flow, 15 of hospitalized flow, and 82 cases of migrant flow. The 1974 cases having complete address records are a sample of the total 5327 SARS cases in the country. The data’s frequency distributions of SARS flow and total cases agree well with each other in various dimensions, such as gender, age and occupation (Additional files 5, 6, 7: Figures S8-10). Therefore, there is no evidence there is systematic bias of the sampling, and the missing data were updated by ratio estimator method (see Additional file 8).
It is clear now that SARS-CoV-2 can be transmitted by human-to-human despite the majority of the early cases had contact history with the Huanan Seafood market 11,18,28. Analysis of 425 patients with confirmed COVID-19 showed that the incubation period is 3 to 7 days. The mean was 5.2 days (95% CI: 4.1 to 7.0), and the 95th percentile of the distribution is 12.5 days (95% CI: 9.2 to 18) 11. Notably, it was reported that the incubation period could be as long as 24 days in a rare case 25. The basic reproductive number (R0) up to the period of 4 Jan 2020 was estimated based on the study of 425 patients to be 2.2 (meaning that one patient has been spreading infection to 2.2 other people) 11, slightly smaller than the value of 2.68 by a modelling in another 29. The R0 of SARS-CoV-2 from both of these two studies is smaller than that of SRAS, which are 3 before public health measures were implemented 30. However, subsequent investigation based on the analysis of high-resolution real-time human travel and infection data estimated that the R0 is much larger, ranging from 4.7 to 6.6 before the control measures 31, implying that SARS-CoV-2 is highly contagious and more infectious than initially estimated. This conclusion is consistent with the wide spread of SARS-CoV-2 within a short period time and was also echoed by the finding that SARS-CoV-2 Spike (S) protein had 10- to 20-fold higher affinity to human angiotensin-converting enzyme 2 (ACE2) receptor than that of SARS-CoV based on the Cryo-EM structure analysis of S proteins 32. Similar to SARS-CoV, the entry of SARS-CoV-2 into host cells depends on the recognition and binding of S protein to ACE2 receptor of the host cells 14,33. The high affinity of S protein to ACE2 receptor likely contributes to the quick spreading of virus. The finding of ACE2 as the receptor of SARS-CoV-2 also indicates that human organs with high ACE2 expression level, such as lung alveolar epithelial cells and enterocytes of the small intestine, are potentially the target of SARS-CoV-2 34.
As a new coronavirus, it is not known yet about how SARS-CoV-2 spreads. Current knowledge for SARS-CoV-2 transmission is largely based on what is known from the similar coronaviruses, particularly SARS-CoV and MERS-CoV, in which human-to-human transmission occurs through droplets, contact and fomites. SARS-CoV is predominantly transmitted through indirect or direct contact with mucous membranes in the mouth, eyes, or nose 35. It has been shown that unprotected eyes and exposed mucous membranes are vulnerable to SARS-CoV transmission 36. A member of the national expert panel on pneumonia was infected by SARS-CoV-2 after the inspection in Wuhan 37. As he wore a N95 mask but not any eye protector, and experienced eye redness before the onset of pneumonia, it was thus suspected that unprotected exposure of the eyes to SARS-CoV-2 might be another transmission pathway 37. However, SARS-CoV-2 was not detected from the conjunctival swab sample in a confirmed COVID-19 patent with conjunctivitis 38, suggesting that more evidences are needed before concluding the conjunctival route as the transmission pathway of SARS-CoV-2. The mode of transmission by MERS-CoV is not well understood but is believed to spread largely via the respiratory close contact route 39,40.
Based on the transmission mode of SARS-CoV and MERS-CoV, a serial of preventive measures have been recommended, including avoiding close contact with people suffering from acute respiratory infections and frequent hand-washing 41. The viruses of SARS-CoV-2 were also detected in the stool samples in some patients but not all 18,22, suggesting that a possible fecal-oral transmission occurs 42. A systematic study showed that viruses could be detected in oral swabs, anal swabs and blood samples of the patients, and the anal swabs and blood could test positive when oral swab tested negative 43. Furthermore, a trend of shift from more oral positive in the collected samples during the early period of patient infection to more anal positive during later period of infection was also found 43. Therefore, a multiple shedding routes of SARS-CoV-2 might exist.
One of the challenges for preventive control of SARS-CoV-2 spreading is that the viruses are likely transmitted by asymptomatic contact. A German businessman was found infected by SARS-CoV-2 after attending a conference together with a colleague, who had no signs or symptoms of infection but had become ill due to the SARS-CoV-2 infection later 44. This observation suggests that infected patients likely start to shed viruses before the onset of any symptom, which undoubtedly will bring great challenge to the current practice of preventive control by measuring body temperature. Despite the claim of the transmission by asymptomatic contact has been challenged 45, other asymptomatic carriers were also observed to transmit the viruses of SARS-CoV-2 46,47. Consistently, a study found that an asymptomatic patient had a similar vial loads in the samples of nasal and throat swabs to that of the symptomatic patients 48.
In the past 15 years China has experienced numerous public health crises caused by disease outbreaks including Severe Acute Respiratory Syndromes (SARS) in 2003 and Influenza A Virus Subtype H7N9 (H7N9) in 2013. Epidemics such as SARS and H7N9 have caused huge negative impacts on population health and the economy. If not controlled well, they can become pandemics, threatening national and even international security. SARS, in particular, highlighted global connectedness and the great threat that pandemic and potential pandemic present.
Since the SARS outbreak in 2003, China has established and strengthened its national and local surveillance systems to prevent and control diseases and has also expanded its laboratory capacity [1, 2]. China's experiences of emergency management for epidemics have varied. Although the SARS coronavirus and H7N9 virus share some similarities, the control efforts for SARS were problematic and the disease spread globally, while the H7N9 response was highly praised and the disease did not spread widely. This article discusses the impacts of SARS in 2003 and H7N9 in 2013 in China, in order to provide a better understanding to government and practitioners of why improving management of response to infectious disease outbreaks is so critical for a country's economy, its society, and its place in the global community.