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Groups of 9 cynomolgus macaques were challenged via the intratracheal and intranasal routes with the recombinant Urbani, GZ02 and HC/SZ/61/03 SARS-CoV strains. No overt clinical symptoms were seen in any of the infected animals. In addition, no fever was detected on clinical exam days 1, 2, 4, 7, 10 and 14 post infection. Minor transient lymphopenia was seen on days 1 and 2 p.i. in all infected animals (data not shown). No significant changes were observed in blood chemistry.
Respiratory disease development was also analyzed by radiographic imaging (X-ray) with first signs of mild interstitial pulmonary infiltration and peribronchial markings in the lungs of some animals infected with Urbani as early as day 1 p.i. (data not shown). On days 2 and 4 p.i. radiological changes in Urbani infected animals were very similar to day 1 with an additional decrease in conspicuity of the caudal vena cava (CVC; Fig. 1). These changes lasted up to day 11 in at least 1 of the animals. Radiological changes in HC/SZ/61/03 infected animals were very similar to Urbani infected animals. Interestingly, one animal showed a clear progression on day 2 with small ventral-most consolidation in left middle/caudal lung (right lateral view) and heavy peribronchial markings (Fig. 1). Notable improvement was seen by day 4 with mild interstitial infiltrates centrally, and unsharp CVC margins on both lateral views. Surprisingly, infection with GZ02 did not result in significant radiological changes early in infection, although mild increase in interstitial infiltrates could be observed in 1 animal on day 2 (Fig. 1).
Gross pathological findings during necropsies on days 1, 4 and 14 p.i. included enlarged cervical and bronchial lymph nodes, splenomegaly and adherence of lung lobes to pleura. No lesions were noticeable on the lungs of any of these animals.
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.
Severe acute respiratory syndrome (SARS) emerged in late 2002, with more than 8096 cases reported by April 21 2004 by the World Health Organization, mostly in China (5327), Taiwan, Hong Kong SAR, Singapore and Canada. There were 774 deaths and a mortality of 9.6%. The largest outbreak was in Beijing, with over 2,521 cases. The SARS-associated coronavirus (SARS-CoV) was identified as the causal agent following its isolation and detection by electron microscopy and reverse transcriptase polymerase chain reaction (RT-PCR) from a range of clinical specimens. Serological evidence of infection has been found in most patients fitting the clinical definition of SARS. The clinical, radiological, and laboratory findings of SARS from Beijing and elsewhere have been described previously.
The aim of this study was to detect and quantify SARS-CoV using RT-PCR in sera and throat washes and stools self-collected by 271 patients with laboratory confirmed SARS managed at a single institution. These samples were collected during the extreme pressure of the Beijing SARS outbreak in the context of healthcare worker concern about the safety of collecting nsaopharyngeal aspirates (NPAs) from ill patients.
A typical characteristic of the SARS-CoV-2 infected patient is pneumonia, now termed as Coronavirus Disease 2019 (COVID-19), demonstrated by computer tomographic (CT) scan or chest X -ray 3,8,18. In the early stages, the patients showed the acute respiratory infection symptoms, with some that quickly developed acute respiratory failure and other serious complications 20. The first three patients reported by the China Novel Coronavirus Investigating and Research Team all developed severe pneumonia and two of these three patients with available clinical profiles showed a common feature of fever and cough 8. A subsequent investigation of a family of six patients in the University of Hong Kong-Shenzhen Hospital demonstrated that all of them had pulmonary infiltrates, with a variety of other symptoms 18. The chest X-ray and CT imaging in a study showed that 75% of 99 patients demonstrated bilateral pneumonia and the remaining 25% unilateral pneumonia 21. Overall, 14% of the patients showed multiple mottling and ground-glass opacity 21. The first cases of coronavirus infection in the United States also showed basilar streaky opacities in both lungs by chest radiography. However, the pneumonia for this patient was only detected on the day 10 of his illness 22. It is also of note that one of patients among the family of six patients did not present any other symptoms and signs, but had ground-glass lung opacities identified by CT scan 18.
At least four comprehensive studies on the epidemiological and clinical characteristics of SARS-CoV-2 infected patients have been performed 21,23-25. The most common signs and symptoms of patients are fever and cough 21,23-25. Fatigue was complained by 96% of patients (n=138) in one study 24, but was less outstanding (18%, n=44) in another report 23. A combinational analysis of the common recorded signs or symptoms of the reported cases found that fever was observed in around 90% of the SARS-CoV-2 infected patients; the number of patients with cough is relatively less (68%) compared to fever (Table 1). In addition, shortness of breath or dyspnea, muscle ache, headache, chest pain, diarrhea, haemoptysis, sputum production, rhinorrhoea, nausea and vomiting, sore throat, confusion, and anorexia were also observed in a proportion of the patients 21,23-25 (Table 1).
A common feature of patients of SARS, MERS or COVID-19 is the presence of severe acute respiratory syndrome; however, the estimated fatality rate of COVID-19 (2.3%) is much lower than SARS (~10%) and MERS (~36%) 26,27. Furthermore, the viruses responsible for above three diseases are evolutionary distinct (See below for details) 19.
Virus replication of all three SARS-CoV strains was mainly restricted to the respiratory tract (trachea, bronchi and lung lobes) and low levels of replication in spleen, cervical and bronchial lymph nodes (Fig. 2A and B). Viral replication peaked in the respiratory tract on day 1 p.i. (Fig. 2A) with a reduction in virus titers and numbers of virus positive tissues on day 4 p.i. (Fig. 2B), similar to our findings in mice. No infectious virus could be isolated on 14 days p.i. in any of the tissues (Data not shown). Virus titers in Urbani infected animals were generally 1 to 2 logs higher compared to GZ02 and HC/SZ/61/03 infected animals. Viral RNA could be detected in the lungs of infected animals up to 14 days p.i. (data not shown). The levels of viral RNA were similar for each SARS-CoV strain at each time point but decreased over time as observed with the viral titers.
As a measure of virus shedding, nasal, oral and rectal swabs were assayed for infectious virus. In nasal swabs, virus titers peaked by day 2 but could be detected up to day 7 and 11 p.i. (Fig. 3A) Virus titers in oral swabs peaked on day 1 and were on or below detectable titers by day 4 p.i. (Fig. 3B). Low levels of virus replication could be observed in rectal swabs but only in a few animals (Fig. 3C).
Between March 26-May 31 2003, 304 patients fitting the case definition of probable SARS were hospitalized. Of these, 271 were laboratory confirmed following the detection of SARS-CoV-specific IgM and/or IgG antibody by immunofluorescence and/or by the detection of SARS-CoV RNA by RT-PCR.
The mean age of the cohort was 36 ± 16 years. There were 92 (33.9%) healthcare workers who acquired SARS, including 51 nurses, 30 physicians, 5 logistics staff, 3 pharmacists and 2 laboratory technicians (one of whom was believed to be infected after handling sputum and stool samples from SARS patients in a diagnostic laboratory). A total of 112 people were infected following exposure to SARS patients in the hospital setting, either as healthcare workers, patients or visitors, and another 62 cases were household contacts of known SARS cases. Common clinical features on admission included fever (100%), subjective shortness of breath (57%), nonproductive cough (55%), malaise (52%), myalgia (38%), headache (30%), dyspnea (21%), chills (17%), diarrhea (11%) and sore throat (6%). The mortality rate was 9.2% (25/271) amongst laboratory-confirmed cases.
Sera, throat washes and stool samples were tested for SARS-CoV RNA by RT-PCR. A total of 614 sera (ranging from 1–7 per patient) were collected 1–78 days after the onset of illness from 271 cases. Overall, 31.3% (192/614) of sera had detectable amounts of SARS-CoV RNA detected, with viral loads ranging from 101-103 copies/ml serum (Table 1). Sera collected within 9 days of disease onset were more likely to be RT-PCR positive (54%) than later in the disease course, although SARS-CoV RNA was still occasionally detected in sera out to 24 days of illness.
A single throat wash was self-collected by 96 patients 1 to 35 days after the onset of disease. A total of 50 (52.1%) had SARS-CoV RNA detected by RT-PCR (Table 2), with viral loads ranging from 101-105 copies/ml wash fluid. The highest detection rate was 61% in throat washes collected between days 5 and 14.
Of 224 stool samples self-collected by 188 patients (1–2 samples each), 127 (56.7%) had SARS-CoV RNA detected by RT-PCR (Table 3). Stool samples were not collected in the first 10 days of illness, but high rates of SARS-CoV RNA detection (44/51, 86.3%) were seen in stools collected between 10 and 19 days after onset. Viral loads in stool were as high as 1010 copies/g feces from day 10. Fecal samples collected 40 days or more after onset of disease contained SARS-CoV RNA in 29.8% (17/57) of samples, with a mean load of 7000 copies/g feces. The fecal load of SARS-CoV was at least between 2 and 3 logs higher than in throat washes or sera at comparable time points.
As more cases of COVID-19 occur, it is becoming established that the most severe cases and mortality are associated with underlying health conditions. The most common associated comorbidities are pulmonary disease, diabetes, and old age (10). Interesting questions as to how these comorbidities impact viral pathogenesis are open for investigation. More severe SARS cases were also associated with age, and work in mice has demonstrated this (12–14). Severe MERS is associated with diabetes and other underlying health conditions (15, 16), and again, work in mice has shown that diabetes can impact the immune response to infection, leading to increased pathogenesis (17). It will be interesting to see whether SARS-CoV-2 infection is similarly impacted.
Until the very end of 2019, there were six coronaviruses known to cause disease in humans. Four of these result in little more than a common cold and are endemic around the world. The viruses known as human coronavirus (hCoV)-229E, hCoV-HKU1, hCoV-NL63, and hCoV-OC43 are of little concern at a global public health level. The other two, however, have caused more widespread concern. In 2002, severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in the human population. In a matter of months, this virus from a bat that transmitted via a palm civet to infect a human in the Guangdong province of China infected over 8,000 people, killing roughly 10% (1). In 2003, SARS-CoV infections stopped, and the virus has not been seen since. A second epidemic coronavirus, known as Middle East respiratory syndrome coronavirus (MERS-CoV), emerged in 2012. Like the SARS-CoV outbreak, MERS-CoV started with a patient suffering pneumonia and came from a zoonotic event (this time from a bat via a camel to a human) (1). However, MERS-CoV has shown far more limited human-to-human transmission than SARS-CoV. Since 2012, there have been roughly 2,500 cases of MERS-CoV, mostly confined to regions of the Middle East. While case numbers are low for MERS-CoV, there is a high case fatality ratio (CFR) of approximately 35%, making this virus one of the deadliest human pathogens. Coronaviruses that infect humans all appear to have respiratory transmission, making them pathogens of pandemic potential. The end of 2019 saw the emergence of a novel human coronavirus that is rapidly spreading around the global and has a higher degree of lethality than the endemic coronaviruses, though not to the level of SARS-CoV or MERS-CoV. The virus was initially named 2019-nCoV but is now termed SARS-CoV-2 and causes the disease COVID-19 (coronavirus disease 2019). At the time of writing, there have been over 115,000 cases and over 4,000 deaths.
The first case of COVID-19 was reported to the WHO by Chinese authorities on 31 December 2019 as a result of a patient suffering pneumonia in Wuhan City, Hubei Province, China. Over the following days, more patients were suspected to be suffering the same disease, and by 9 January, a novel coronavirus had been detected and the sequence was published online shortly thereafter (2). The 2 months since emergence of SARS-CoV-2 have demonstrated the rapid pace at which a virus can spread and which science can develop. After an initial lag phase, cases of COVID-19 followed a closely exponential curve. The vast majority of cases are, at the time of writing, still from mainland China. However, over 100 other countries have reported cases. Most cases outside China have been associated with travel to that country, but more clusters of cases are now being detected without travel history. In this article, we will discuss what has already been learned about the virus and will then outline 10 key questions and directions of study for this novel coronavirus.
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),,,.
Following reports of the last case of the severe acute respiratory syndrome (SARS) epidemic in July 2003, there has been remarkable progress in several areas of research on the molecular identification of the pathogen and its pathogenesis, replication, genetics, and host immunogenicity, as well as elegant epidemiological studies. The sequence of epidemiological events that unfolded early in the outbreak gave researchers a glimpse into the first new pathogen of the era of globalization. As the year 2002 drew to a close, multiple reports of an "infectious atypical pneumonia" caught public health officials across the globe by surprise and suggested that a new human pathogen had emerged in the Guangdong Province in China. By the end of February 2003, this outbreak of SARS had infected almost 800 patients and caused 31 deaths in the Province. One month later, the disease had spread throughout Asia and into Europe and North America. This epidemic eventually affected more than 8000 people and resulted in approximately 800 deaths worldwide, with mortality rates reaching over 40% in certain populations.
Electron microscope analysis quickly identified the putative SARS agent as having features associated with coronaviruses. The SARS agent was later unambiguously identified as a new coronavirus member and named SARS-coronavirus (SARS-CoV). Coronaviruses are enveloped, plus-stranded RNA viruses with the largest RNA genomes known (on the order of 30 kb). Coronaviruses have long been important in the world of veterinary viral diseases. However, previously known human coronaviruses such as HCoV-229E and HCoV-OC43 cause only minor health problems such as the common cold and gastrointestinal diseases. In contrast, the SARS-CoV pathogen causes fever, pulmonary edema, and diffuse alveolar damage in severely affected individuals (collectively termed severe acute respiratory syndrome). SARS-CoV is also a unique coronavirus in that, to date, it is the only member known to cause severe morbidity and mortality in humans. Demonstration that SARS-CoV can cause serious public health problems has focused attention on the need to understand the viral replicative strategy and devise prophylactic measures.
The clinical symptoms of SARS are those of a lower respiratory tract infection and are accompanied by damage to the lungs. Gastrointestinal involvement is also common, with more than 20% of patients presenting with watery diarrhea. Fecal samples from SARS patients taken up to 25 days after onset of disease contain viral RNA, which suggests viral shedding through the bowels. Liver dysfunction has also been reported based on observed necrosis in hepatocytes. Post-mortem tissue examination of SARS patients has found the virus presence in lung, bowel, lymph node, liver, heart, kidney, and skeletal muscle samples. The primary mode of SARS-CoV transmission is airborne via droplets. However, there are also reports of the presence of replicating virus in blood cells (peripheral blood mononuclear cells) and in the small and large intestine. Alternative modes of transmission, such as blood-borne or fecal-oral are therefore possible.
The virus has been isolated from wild animals (Himalayan palm civets and raccoon dogs) found in the animal markets of Guangdong, China. The actual natural reservoir for SARS-CoV is still unknown. Once transmitted to humans, SARS-CoV appears to evolve to facilitate to human-human transmission. Sequence analysis of different SARS-CoV isolates from early in the epidemic show deletion events occurring in open reading frame 8 (Orf 8). Identical deletions in Orf 8 have also been seen in animal coronaviruses supporting the idea that SARS-CoV was introduced to humans via an animal intermediate. In addition to deletion events occurring early and late in the epidemic, a slowing of missense mutations is seen over time, with the most extensive changes occurring in the S protein during the early stages of the outbreak. This suggests the virus has undergone some level of adaptation but has ultimately stabilized at a time in the epidemic where SARS-CoV has become more virulent. Deciphering the evolutionary passage of this virus will undoubtedly provide valuable information on preventing future outbreaks.
In the wake of the SARS epidemic, a number of excellent review articles on the clinical and molecular aspects of SARS epidemiology have been published. These reviews have focused primarily on rapid advances made in the identification and characterization of SARS-CoV genomes as well as describing the etiology of the virus and clinical features of the disease. Now the SARS-CoV story has entered a new phase, a search for preventative strategies and a cure. In this review, we highlight the progress made in revealing the molecular aspects of SARS-CoV biology and how such information may lead to strategies for disease prevention.
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 %).
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.
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.
Currently, the most widely accepted MERS laboratory animal model is the rhesus macaque (Macaca mulatta). MERS‐CoV infection can lead to a pneumonia‐like syndrome within 24 hours of challenge in the rhesus macaque, but it is not as severe as in humans.24 In some studies on MERS infection in rhesus macaques,24, 25 following intraoral, intranasal and intravascular inoculation with 7 × 106 TCID50, acute, transient and mild to moderate respiratory symptoms such as tachypnea, deep abdominal breathing, coughing, fever and anorexia were presented. However, gross lesions were only visible in the lungs. Microscopically, these were typical bronchointerstitial pneumonia or interstitial pneumonia. Another experiment26 used an intravascularly inoculated infection dose of 6.5 × 107 TCID50, which resulted in pulmonary congestion and the microscopic lesions of interstitial pneumonia. After infection, MERS‐CoV RNA was identified in nasal swabs and bronchoalveolar lavage samples and partially in oropharyngeal swabs. Inside the body, it was present only in the lungs, and not in blood or any visceral organs, even the kidneys.3, 24, 27 Additionally, all blood count abnormalities in the rhesus macaques were like those reported in human cases.
In contrast to the results found for MERS‐CoV, rhesus macaques developed different symptoms after being challenged with different SARS‐CoV lineages. Rhesus macaques infected with the Tor 2 lineage28 by intravascular inoculation exhibited clinical signs ranging from symptom‐free to agitated and aggressive. Focal pulmonary consolidation was revealed microscopically. The Urbani lineage, on the other hand, could not successfully infect rhesus macaques. In addition, rhesus macaques showed obvious clinical signs and histopathology after inoculation with the PUMC01 lineage.29 The animal's age is the key factor affecting these results, but this is hard to identify in wild‐caught monkeys.
In December 2019, a cluster of pneumonia cases, caused by a newly identified β-coronavirus, occurred in Wuhan, China. This coronavirus, was initially named as the 2019-novel coronavirus (2019-nCoV) on 12 January 2020 by World Health Organization (WHO). WHO officially named the disease as coronavirus disease 2019 (COVID-19) and Coronavirus Study Group (CSG) of the International Committee proposed to name the new coronavirus as SARS-CoV-2, both issued on 11 February 2020. The Chinese scientists rapidly isolated a SARS-CoV-2 from a patient within a short time on 7 January 2020 and came out to genome sequencing of the SARS-CoV-2. As of 1 March 2020, a total of 79,968 cases of COVID-19 have been confirmed in mainland China including 2873 deaths. Studies estimated the basic reproduction number (R0) of SARS-CoV-2 to be around 2.2, or even more (range from 1.4 to 6.5), and familial clusters of pneumonia outbreaks add to evidence of the epidemic COVID-19 steadily growing by human-to-human transmission.
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.
Prior to the development of therapeutic regimes based on molecular mechanisms of the disease, the causative agent had to be isolated and analysed. Soon after the fast establishment of the international WHO laboratory network, rapid progress was made in the identification process of the causative agent, and it was reported that SARS is most probably caused by a novel strain of the family of coronaviruses. These viruses are commonly known to cause respiratory and gastrointestinal diseases of humans and domestic animals. The group of coronaviruses is classified as a member of the order nidovirales, which represents a group of enveloped positive-sense RNA viruses consisting of coronaviridae and arteriviridae. Viruses of this group are known to synthesize a 3' co-terminal set of subgenomic mRNAs in the infected cells.
Since the first pneumonia patient was identified around December 2019, in Wuhan, China, multiple human cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. The 2019 novel coronavirus disease (COVID-19) has now swept through the continents and poses a global threat to public health. Up till 12th March 2020, at least 80,980 cases in China and 43,538 cases beyond China were confirmed, covering 118 countries, areas or territories.
Many infections amongst medical staff have been reported, of whom three ophthalmologists from Wuhan Central Hospital died of COVID-19 due to occupational exposure, and Dr. Guangfa Wang, a pneumonia expert, was infected by SARS-CoV-2 through unprotected eye exposure. These events raise an alarm on the route of SARS-CoV-2 transmission. Faced with the possibility of ocular transmission, ophthalmologists are very likely to contract the infection. Drawing on the rich experience during the previous SARS outbreak, the Chinese government has promptly released various protection measures for ophthalmology, and recommended protection for the eyes, as well as mouth and nose, when caring for patients potentially infected with SARS-CoV-2. The American Academy of Ophthalmology recently published a similar recommendation for ophthalmologists from the Centers for Disease Control and Prevention (CDC). Based on the latest published literatures, guidelines and clinical practice experience in domestic hospitals, we have summarized the Chinese experience through the lens of ophthalmology, hoping to make a contribution to protecting ophthalmologists and patients around the world, and praying that the pandemic will be contained as soon as possible.
The mean incubation period of SARS was estimated to be 6.4 days (95% confidence interval, 5.2 to 7.7). The mean reported time from the onset of clinical symptoms to the hospital admission varied between three and five days.
Main clinical features of the disease are in the initial period common symptoms such as persistent fever, myalgia, chills, dry cough, dizziness, and headache. Further, although less common symptoms are sore throat, sputum production, coryza, vomiting or nausea, and diarrhea. Special attention has been paid to the symptom of diarrhea: Watery diarrhea has also been reported in a subgroup of patients one week after the initial symptoms.
The clinical course of the disease seems to follow a bi- or triphasic pattern. In the first phase viral replication and an increasing viral load, fever, myalgia, and other systemic symptoms can be found. These symptoms generally improve after a few days. In the second phase representing an immunopathologic imbalance, major clinical findings are oxygen desaturation, a recurrence of fever, and clinical and radiological progression of acute pneumonia. This second phase is concomitant with a fall in the viral load. The majority of patients is known to respond in the second phase to treatment. However, about 20% of patients may progress to the third and critical phase. This phase is characterized by the development of an acute respiratory distress syndrome (ARDS) commonly necessitating mechanical ventilation.
Another suitable and well‐established model is the common marmoset (Saguinus mystax), which can show more severe clinical signs than rhesus macaques when infected with MERS‐CoV.30, 31, 32 When administered through a combination of intraoral, intranasal and intravascular inoculation, with doses ranging from 5 × 106 TCID50 to 5 × 107 PFU, mild to moderate respiratory disease was observed, and interstitial pneumonia was observed clinically and microscopically.
When infected with SARS‐CoV, common marmosets exhibit fever, diarrhea, multifocal pneumonitis and hepatis.33 Research using this model is progressing. The common marmoset is a potential non‐human primate model for SARS‐CoV infection and deserves more attention.
Based on the current information, most patients had a good prognosis, while a few patients were in critical condition, especially the elderly and those with chronic underlying diseases. As of 1 March 2020, a total of 79,968 confirmed cases, including 14,475 (18.1%) with severe illness, and 2873 deaths (3.5%) in mainland China had been reported by WHO. Complications included acute respiratory distress syndrome (ARDS), arrhythmia, shock, acute kidney injury, acute cardiac injury, liver dysfunction and secondary infection. The poor clinical outcome was related to disease severity. The disease tends to progress faster in elderly people, with the median number of days from the occurrence of the first symptoms to death shorter among people aged 65 years or more [56, 57]. Similar to H7N9 patients, the elderly male with comorbidities and ARDS showed a higher death risk. Additionally, more than 100 children were infected, with the youngest being 30 h after birth. Neonates and the elderly need more attention and care due to their immature or weak immune system.
We searched MEDLINE, ScienceDirect, Embase, the Cochrane Library, WanFang Database, VIP Database, SinoMed, China National Knowledge Infrastructure (CNKI), the CDC for COVID-19 website (https://www.cdc.gov/coronavirus/2019-ncov/publications.htm), Chinese Scientific Research Academic Exchange Platform for COVID-19 (http://medjournals.cn/2019NCP/index.do), and relevant references for papers related to "ophthalmology and SARS-CoV-2/COVID-19"; published till 12th March 2020. The search strategy was as follows: (SARS-CoV-2 or 2019-nCov or COVID-19 or NCP or coronavirus or "severe acute respiratory syndrome coronavirus 2" [Supplementary Concept] or "COVID-19" [Supplementary Concept]) and (ocular or eye or ophthalm* or ophthalmologist or tear or conjunctiv* or "Conjunctivitis"[Mesh] or "Conjunctivitis, Viral"[Mesh]).
We identified 33 articles in total published by Chinese scholars directly relevant to ophthalmology and SARS-CoV-2/COVID-19. Twenty-seven articles are published in Chinese journals, most articles are reviews, almost all regarding ophthalmic precautions and ocular surface transmission of SARS-CoV-2 infection (Table 1).
Since December 2019, an increasing number of patients with pneumonia of unknown etiology in Wuhan, a city with 11 million people, have alarmed the local hospital. On 29 December 4 cases were linked to Huanan Seafood wholesale market 9, where non-aquatic live animals, including several kinds of wild animals, were also on the sales. The local Center for Disease Control (CDC) then found additional patients linked to the same market after investigation, and reported to China CDC on 30 Dec 2019 9. The second day, World Health Organization (WHO) was informed of the cases of pneumonia of unknown etiology by China CDC 10. On 6 Jan 2020, a level 2 emergency response was launched by China CDC 11.
The causal agent was not identified until 7 Jan 2020; a new type of coronavirus was isolated by Chinese authority 10. The genome sequence of SARS-CoV-2 (WH-Human_1) was first released and shared by China on 10 Jan 12. The isolation and identification of SARS-CoV-2 apparently facilitated the development of molecular diagnostic methods and the confirmation of the infected patients. As of 21 Jan, there are 270 cases were confirmed from Wuhan 13. On 23 Jan, Wuhan city was locked down by local government. On 30 Jan, WHO declared a “public health emergency of international concern” (Fig. 1).
Subsequently, the viruses were successfully isolated from several laboratories 8,14,15. The virion of SARS-CoV-2 looks like a solar corona by transmission electron microscopy imaging: the virus particle is in a spherical shape with some pleomorphism; the diameter of the virus particles range from 60 to 140 nm with distinctive spikes about 8 to 12 nm in length 8. The observed morphology of SARS-CoV-2 is consistent with the typical characteristics of the Coronaviridae family. The genome sequence of SARS-CoV-2 from clinical samples has been obtained by several laboratories with deep sequencing 8,14-18. The viral genome of SARS-CoV-2 is around 29.8 kilobase, with a G+C content of 38%, in total consisting of six major open reading frames (ORFs) common to coronaviruses and a number of other accessory genes 14,16. The sequences analysis showed that the genome sequences of viruses from different patients are very conserved 14,15,19, implying that the human virus evolves recently.
Clustered onset often happens in the same family or from the same gathering or vehicle such as a cruise ship. Patients often have a history of travel or residence in Wuhan or other affected areas or contact with infected individuals or patients in the recent two weeks before the onset 50. However, it has been reported that people can carry the virus without symptoms longer than two weeks and cured patients discharged from hospitals can carry the virus again 51, which sends out an alarm to increase the time for quarantine.
Fever is often the major and initial symptom of COVID-19, which can be accompanied by no symptom or other symptoms such as dry cough, shortness of breath, muscle ache, dizziness, headache, sore throat, rhinorrhea, chest pain, diarrhea, nausea, and vomiting. Some patients experienced dyspnea and/or hypoxemia one week after the onset of the disease 8. In severe cases, patients quickly progressed to develop acute respiratory syndrome, septic shock, metabolic acidosis, and coagulopathy. Patients with fever and/or respiratory symptoms and acute fever, even without pulmonary imaging abnormalities, should be screened for the virus for early diagnosis 39-41.
A demographic study in late December of 2019 showed that the percentages of the symptoms were 98% for fever, 76% for dry cough, 55% for dyspnea, and 3% for diarrhea; 8% of the patients required ventilation support 42. Similar findings were reported in two recent studies of a family cluster and a cluster caused by transmission from an asymptomatic individual 43,44. Comparably, a demographic study in 2012 showed that MERS-CoV patients also had fever (98%), dry cough (47%), and dyspnea (55%) as their main symptoms. However, 80% of them required ventilation support, much more than COVID-19 patients and consistent with the higher lethality of MERS than of COVID-19. Diarrhea (26%) and sore throat (21%) were also observed with MERS patients. In SARS patients, it has been demonstrated that fever (99%-100%), dry cough (29%-75%), dyspnea (40%-42%), diarrhea (20-25%), and sore throat (13-25%) were the major symptoms and ventilation support was required for approximately 14%-20% of the patients 45.
By February 14, the mortality of COVID-19 was 2% when the confirmed cases reached 66,576 globally. Comparably, the mortality of SARS by November 2002 was 10% of 8,096 confirmed cases 46. For MERS, based on a demographic study in June 2012, the mortality was 37% of 2,494 confirmed cases 47. An earlier study reported that the R0 of SARS-CoV-2 was as high as 6.47 with a 95% confidence interval (CI) of 5.71-7.23 48, whereas the R0 of SARS-CoV only ranged from 2 to 4 49. A comparison of SARS-CoV-2 with MERS-CoV and SARA-CoV regarding their symptoms, mortality, and R0 is presented in Table 1. The above figures suggest that SARS-CoV-2 has a higher ability to spread than MERS-CoV and SARS-CoV, but it is less lethal than the latter two 6. Thus, it is much more challenging to control the epidemic of SARS-CoV-2 than those of MERS-CoV and SARS-CoV.