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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.
A very important question for understanding SARS-CoV-2 infection is what systems can be used for study. Early studies on SARS-CoV-2 determined that the cellular receptor for the virus is ACE2, similarly to SARS-CoV (3). This knowledge helps to develop an understanding of susceptibility of certain in vitro cell lines to infection with the novel virus. The likelihood is that if cells were not permissive for growth of SARS-CoV, they probably will not support growth of SARS-CoV-2. As more labs around the world start researching the new virus, a better understanding of the permissive cell lines will be developed, an important step to testing therapeutic options and developing a better understanding of basic aspects of SARS-CoV-2 virology. The more challenging aspect of lab-based research on the novel human coronavirus will be developing small-animal models. The early research on receptor usage suggests the virus is not able to infect cells expressing mouse ACE2 (3), thus making a mouse model potentially challenging. Whether expression of human ACE2 in mouse lungs using adenovirus or mouse adaptation of SARS-CoV-2 can develop appropriate models, as was done for SARS-CoV (18), is a pressing question. Whether other small-animal models can be used also needs to be investigated. These models will be essential for thoroughly testing therapeutic candidates and vaccine strategies and understanding the pathology of disease.
Virus isolation by cell culture is used extensively as a traditional technique in virology. Coronavirus presenting in the clinical specimens of SARS patients was detected by inoculating the clinical specimens in cell cultures to allow the infection and the subsequent isolation of the virus. Fetal rhesus kidney (FRhK-4; ref. 2) and vero cells (3) were found to be susceptible to SARS-CoV infection. After the isolation procedure, the pathogen was identified as the SARS-CoV by further tests, such as electron microscopy, RT-PCR, or immunofluorescent viral antigen detection. Virus isolation is the only means to detect the existence of live virus from the tissue. The methodology is generally employed only for a preliminary identification of an unknown pathogen, as the procedure requires skillful technicians and is time consuming. The requirement of infectious viruses and that the duration of live virus existence varies add on further problems for conducting such assays, but they are nevertheless of very high specificity.
There is no available vaccine against COVID-19, while previous vaccines or strategies used to develop a vaccine against SARS-CoV can be effective. Recombinant protein from the Urbani (AY278741) strain of SARS-CoV was administered to mice and hamsters, resulted in the production of neutralizing antibodies and protection against SARS-CoV,. The DNA fragment, inactivated whole virus or live-vectored strain of SARS-CoV (AY278741), significantly reduced the viral infection in various animal models,,,,,. Different other strains of SARS-CoV were also used to produce inactivated or live-vectored vaccines which efficiently reduced the viral load in animal models. These strains include, Tor2 (AY274119),, Utah (AY714217), FRA (AY310120), HKU-39849 (AY278491),, BJ01 (AY278488),, NS1 (AY508724), ZJ01 (AY297028), GD01 (AY278489) and GZ50 (AY304495). However, there are few vaccines in the pipeline against SARS-CoV-2. The mRNA based vaccine prepared by the US National Institute of Allergy and Infectious Diseases against SARS-CoV-2 is under phase 1 trial. INO-4800-DNA based vaccine will be soon available for human testing. Chinese Centre for Disease Control and Prevention (CDC) working on the development of an inactivated virus vaccine,. Soon mRNA based vaccine’s sample (prepared by Stermirna Therapeutics) will be available. GeoVax-BravoVax is working to develop a Modified Vaccina Ankara (MVA) based vaccine. While Clover Biopharmaceuticals is developing a recombinant 2019-nCoV S protein subunit-trimer based vaccine.
Although research teams all over the world are working to investigate the key features, pathogenesis and treatment options, it is deemed necessary to focus on competitive therapeutic options and cross-resistance of other vaccines. For instance, there is a possibility that vaccines for other diseases such as rubella or measles can create cross-resistance for SARS-CoV-2. This statement of cross-resistance is based on the observations that children in china were found less vulnerable to infection as compared to the elder population, while children are being largely vaccinated for measles in China.
The novel coronavirus originated from the Hunan seafood market at Wuhan, China where bats, snakes, raccoon dogs, palm civets, and other animals are sold, and rapidly spread up to 109 countries. The zoonotic source of SARS-CoV-2 is not confirmed, however, sequence-based analysis suggested bats as the key reservoir. DNA recombination was found to be involved at spike glycoprotein which assorted SARS-CoV (CoVZXC21 or CoVZC45) with the RBD of another Beta CoV, thus could be the reason for cross-species transmission and rapid infection. According to phylogenetic trees, SARS-CoV is closer to SARS-like bat CoVs. Until now, no promising clinical treatments or prevention strategies have been developed against human coronaviruses. However, the researchers are working to develop efficient therapeutic strategies to cope with the novel coronaviruses. Various broad-spectrum antivirals previously used against influenza, SARS and MERS coronaviruses have been evaluated either alone or in combinations to treat COVID-19 patients, mice models, and clinical isolates. Remdesivir, Lopinavir, Ritonavir, and Oseltamivir significantly blocked the COVID-19 infection in infected patients. It can be cocluded that the homologus recombination event at the S protein of RBD region enhanced the transmission ability of the virus. While the decision of bring back the nationals from infected area by various countries and poor screening of passengers, become the leading cause of spreading virus in others countries.
Most importantly, human coronaviruses targeting vaccines and antiviral drugs should be designed that could be used against the current as well as future epidemics. There are many companies working for the development of effective SARS-CoV-2 vaccines, such as Moderna Therapeutics, Inovio Pharmaceuticals, Novavax, Vir Biotechnology, Stermirna Therapeutics, Johnson & Johnson, VIDO-InterVac, GeoVax-BravoVax, Clover Biopharmaceuticals, CureVac, and Codagenix. But there is a need for rapid human and animal-based trails as these vaccines still require 3–10 months for commercialization. There must be a complete ban on utilizing wild animals and birds as a source of food. Beside the development of most efficient drug, a strategy to rapidly diagnose SARS-CoV-2 in suspected patient is also required. The signs and symptoms of SARS-CoV-2 induced COVID-19 are a bit similar to influenza and seasonal allergies (pollen allergies). Person suffering from influenza or seasonal allergy may also exhibit temprature which can be detected by thermo-scanners, hence the person will become suspected. Therefore, an accurate and rapid diagnostic kit or meter for detection of SARS-CoV-2 in suspected patients is required, as the PCR based testing is expensive and time consuming. Different teams of Chinese doctors should immediately sent to Eurpean and other countries, especially spain and Italy to control the over spread of COVID-19, because Chinese doctors have efficiently controlled the outbreak in china and limited the mortality rate to less than 3% only. The therapeutic strategies used by Chinese, should also be followed by other countries.
The N protein is usually chosen as the antigen for anticoronavirus antibody detection assay 91., 92. as it is believed to be a predominant antigen of the SARS-CoV 35., 36.. It is also the only viral protein recognized by acute and early convalescent sera from patients recovering from SARS (29). In addition to the N protein, the S protein in the SARS-CoV was also reported as an antigen eliciting antibodies in human body (29), but at a much lower titer than that of the N protein 35., 36..
The assay based on the presence of SARS-CoV antibodies is suggested to be valid only for specimens obtained more than three weeks after the onset of fever 88., 89., although some patients have detectable SARS-CoV antibodies within 14 days of the onset of illness. Nevertheless, the negative result, i.e. absence of SARS-CoV antibodies, within the first three weeks cannot conclude that the patient is free of the virus, though the ELISA method was still defined as a good standard for rapid diagnosis of SARS (85). Seroconversion from negative to positive or a four-fold rise in antibody titer from acute to convalescent serum indicates recent infection (http://www.who.int/csr/sars/diagnostictests/en/).
An effective strategy to contain virus spread is vaccination. During the SARS-CoV and MERS-CoV outbreaks, much research went into developing vaccine strategies (23). However, the cessation of the SARS epidemic and the minimal human-to-human transmission of MERS-CoV have curtailed the testing of these interventions in humans. With the emergence of SARS-CoV-2, a new impetus into development of coronavirus vaccines has been generated. There are several platforms being used to develop vaccines against SARS-CoV-2, including spike subunit, DNA, RNA, whole-virion, and nanoparticle vaccines. Future testing in cells and animal models will determine which is most likely to be successful in humans.
The viral research institution in China has conducted preliminary identification of the SARS-CoV-2 through the classical Koch’s postulates and observing its morphology through electron microscopy. So far, the golden clinical diagnosis method of COVID-19 is nucleic acid detection in the nasal and throat swab sampling or other respiratory tract samplings by real-time PCR and further confirmed by next-generation sequencing.
SARS-CoV-2 is an emerging pathogen, without any effective drug available for treatment at the moment. It spreads quickly and can result in death of the infected patients. Despite the current mortality rate is 2.3% 26, the emergence of large number of infected patients within short period of time could result in the collapse of health care system, and thus the mortality rate might be elevated. Effective preventive measures must be implemented to control it from global spreading. In addition, great effort should be made on the development of vaccine and antiviral drugs. Meanwhile, the intermediate host and the molecular mechanism of its cross-species spread should be further investigated. Legislation should be employed to prohibit the trade of wild animals, the potential intermediate host(s) of various viruses, to prevent the outbreak of this and other novel viruses in future.
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.
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.
A recent study led by Prof. Nan-Shan Zhong’s team, by sampling 1099 laboratory-confirmed cases, found that the common clinical manifestations included fever (88.7%), cough (67.8%), fatigue (38.1%), sputum production (33.4%), shortness of breath (18.6%), sore throat (13.9%), and headache (13.6%). In addition, a part of patients manifested gastrointestinal symptoms, with diarrhea (3.8%) and vomiting (5.0%). The clinical manifestations were in consistence with the previous data of 41, 99, and 138 patients analysis in Hubei province [46, 48, 50]. Fever and cough were the dominant symptoms whereas upper respiratory symptoms and gastrointestinal symptoms were rare, suggesting the differences in viral tropism as compared with SARS-CoV, MERS-CoV, and influenza. The elderly and those with underlying disorders (i.e., hypertension, chronic obstructive pulmonary disease, diabetes, cardiovascular disease), developed rapidly into acute respiratory distress syndrome, septic shock, metabolic acidosis hard to correct and coagulation dysfunction, even leading to the death (lower panel, Fig. 1).
In laboratory examination results, most patients had normal or decreased white blood cell counts, and lymphocytopenia [16, 54]. But in the severe patients, the neutrophil count, D-dimer, blood urea, and creatinine levels were higher significantly, and the lymphocyte counts continued to decrease. Additionally, inflammatory factors (interleukin (IL)-6, IL-10, tumor necrosis factor-α (TNF-α) increase, indicating the immune status of patients. The data showed that ICU patients had higher plasma levels of IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (GCSF), 10 kD interferon-gamma-induced protein (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and TNF-α.
Moreover, the CT imaging showed that computed tomography on the chest was ground-glass opacity (56.4%) and bilateral patchy shadowing (51.8%), sometimes with a rounded morphology and a peripheral lung distribution, analyzed from the patients in the Fifth Affiliated Hospital, Sun Yat-Sen University. Clinicians have been aware that, a part of confirmed patients appeared the normal CT image presentations. The diagnostic sensitivity of radiologic is limited, so it is necessary to verify with clinical symptoms and virus RNA detections.
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.
The 2019-nCoV causes an ongoing outbreak of lower respiratory tract disease called novel coronavirus pneumonia (NCP) by the Chinese government initially. The disease name was subsequently recommended as COVID-19 by the World Health Organization. Meanwhile, 2019-nCoV was renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses. As of February 24, 2020, more than 80,000 confirmed cases including more than 2,700 deaths have been reported worldwide, affecting at least 37 countries. The WHO has declared this a global health emergency at the end of January 2020. The epicenter of this ongoing outbreak is in the city of Wuhan in Hubei Province of central China and the Huanan seafood wholesale market was thought to be at least one of the places where SARS-CoV-2 from an unknown animal source might have crossed the species barrier to infect humans.
A pioneering study conducted in the city of Shenzhen near Hong Kong by a group of clinicians and scientists from the University of Hong Kong has provided the first concrete evidence for human-to-human transmission of SARS-CoV-2. This is an excellent example of how a high-quality clinical study can make a major difference in policy setting. Several important clinical features of COVID-19 have also been documented in this study. First, an attack rate of 83% within the family context is alarmingly high, indicating the high transmissibility of SARS-CoV-2. Second, the clinical manifestations of COVID-19 in this family range from mild to moderate, with more systematic symptoms and more severe radiological abnormalities seen in older patients. Generally, COVID-19 appears to be less severe than SARS. Third, an asymptomatic child was found to have ground-glass opacities in his lung and SARS-CoV-2 RNA in his sputum sample. This finding of asymptomatic virus shedding raises the possibility for transmission of SARS-CoV-2 from asymptomatic carriers to others, which is later confirmed by others. Finally, the presentation of diarrhea in two young adults from the same family also suggests the possibility for gastrointestinal involvement in SARS-CoV-2 infection and fecal–oral transmission. The study has set the stage for the control and management of COVID-19. The work was completed timely and the investigators showed great courage and leadership in a very difficult time when the Chinese authority failed to recognize widespread person-to-person transmission of SARS-CoV-2 before January 20, 2020.
Several interesting papers on SARS-CoV-2 and COVID-19 have been published in the past few weeks to report on the evolutionary reservoir, possible intermediate host and genomic sequence of SARS-CoV-2 as well as clinical characteristics of COVID-19 [6, 7]. In view of these findings and the urgent needs in the prevention and control of SARS-CoV-2 and COVID-19, in this commentary we highlight the most important research questions in the field from our personal perspectives.
The first question concerns how SARS-CoV-2 is transmitted currently in the epicenter of Wuhan. In order to minimize the spreading of SARS-CoV-2, China has locked down Wuhan and nearby cities since January 23, 2020. The unprecedented control measures including suspension of all urban transportation have apparently been successful in preventing further spreading of SARS-CoV-2 to other cities. However, the number of confirmed cases in Wuhan continued to rise. It is therefore crucial to determine whether the rise is due to a large number of infected individuals before the lock down and/or failure in the prevention of widespread intra-familial, nosocomial or community transmission. Based on the number of exported cases from Wuhan to cities outside of mainland China, it was predicted that there might be more than 70,000 individuals infected with SARS-CoV-2 on January 25, 2020 in Wuhan. This should be determined experimentally in Wuhan as discussed below and it will reveal whether the real numbers of infected people and asymptomatic carriers are indeed underestimated severely. In addition to viral RNA detection, measurement of IgM and IgG antibodies as well as antigens would be very helpful. Several representative residential areas should be selected for detailed analysis so that a big picture can be deduced. The analysis should include all healthy and diseased individuals within the area with the aim of identifying people who have recovered from an infection or are having an active infection. The ratio of asymptomatic carriers should also be determined. The analysis should also be extended to detect RNA and antigen of influenza viruses. The activity of seasonal flu in Wuhan also reached a peak at the beginning of 2020. It will be of interest to see whether the flu season had ended and how many people having a fever now are actually infected with influenza virus. Precision control measures for SARS-CoV-2 should be tailor-designed for high-risk groups based on the results of this analysis. Differentiating people having a flu and preventing them from infecting with SARS-CoV-2 in a hospital setting might also be critical.
The second question is how transmissible and pathogenic is SARS-CoV-2 in tertiary and quaternary spreading within humans. Continued transmission of SARS-CoV-2 in Wuhan suggests that tertiary and quaternary spreading has occurred. Compared to the primary and secondary spreading during which SARS-CoV-2 was transmitted from animal to human and from human to human, has the transmission rate increased and has the pathogenicity decreased? Alternatively, is the virus less transmissible after several passages in humans? Retrospective analysis of all confirmed cases in Wuhan should be very informative. The answers to the above questions hold the key to the outcome of the outbreak. If the transmission is weakened, the outbreak may ultimately come to an end at which SARS-CoV-2 is eradicated from humans. On the contrary, if effective transmission can be sustained, the chance is increased that SARS-CoV-2 will become another community-acquired human coronavirus just like the other four human coronaviruses (229E, OC43, HKU1 and NL63) causing common cold only. The basic reproductive number (R0) of SARS-CoV-2 has been estimated to be 2.68, resulting in an epidemic doubling time of about 6.4 days. Other estimates of R0 could go up to 4, higher than that of SARS-CoV, which is lower than 2. Determining the real R0 will shed light on whether and to what extent infection control measures are effective.
The third question relates to the importance of asymptomatic and presymptomatic virus shedding in SARS-CoV-2 transmission. Asymptomatic and presymptomatic virus shedding posts a big challenge to infection control [1, 2]. In addition, patients with mild and unspecific symptoms are also difficult to identify and quarantine. Notably, the absence of fever in SARS-CoV-2 infection (12.1%) is more frequent than in SARS-CoV (1%) and Middle East respiratory syndrome coronavirus (MERS-CoV; 2%) infection. In light of this, the effectiveness of using fever detection as the surveillance method should be reviewed. However, based on previous studies of influenza viruses and community-acquired human coronaviruses, the viral loads in asymptomatic carriers are relatively low. If this is also the case for SARS-CoV-2, the risk should remain low. Studies on the natural history of SARS-CoV-2 infection in humans are urgently needed. Identifying a cohort of asymptomatic carriers in Wuhan and following their viral loads, clinical presentations and antibody titers over a time course will provide clues as to how many of the subjects have symptoms in a later phase, whether virus shedding from the subjects is indeed less robust, and how often they might transmit SARS-CoV-2 to others.
The fourth question relates to the importance of fecal–oral route in SARS-CoV-2 transmission. In addition to transmission via droplets and close contact, fecal–oral transmission of SARS-CoV has been shown to be important in certain circumstances. Gastrointestinal involvement of SARS-CoV-2 infection and isolation of SARS-CoV-2 from fecal samples of patients are in support of the importance of fecal–oral route in SARS-CoV-2 transmission. Although diarrhea was rarely seen in studies with large cohorts [6, 7], the possibility of SARS-CoV-2 transmission via sewage, waste, contaminated water, air condition system and aerosols cannot be underestimated, particularly in cases such as the Diamond Princess cruise ship with 3,700 people, among whom at least 742 have been confirmed to be infected with SARS-CoV-2 plausibly as the result of a superspreading event. Further investigations are required to determine the role of fecal–oral transmission in these cases and within the representative residential areas selected for detailed epidemiological studies in Wuhan as discussed earlier.
The fifth question concerns how COVID-19 should be diagnosed and what diagnostic reagents should be made available. RT-PCR-based SARS-CoV-2 RNA detection in respiratory samples provides the only specific diagnostic test at the initial phase of the outbreak. It has played a very critical role in early detection of patients infected with SARS-CoV-2 outside of Wuhan, implicating that widespread infection of the virus had occurred in Wuhan at least as early as the beginning of 2020. This has also pushed the Chinese authority to acknowledge the severity of the situation. Due to difficulties in sampling and other technical issues in this test, at one point in early February clinically diagnosed patients with typical ground glass lung opacities in chest CT were also counted as confirmed cases in order to have the patients identified and quarantined as early as possible. ELISA kits for detection of IgM and IgG antibodies against N and other SARS-CoV-2 proteins have also been available more recently. This has made specific diagnosis of ongoing and past infection possible. Particularly, seroconversion for IgM antibodies normally occurs a few days earlier than that of IgG. ELISA reagents for detection of SARS-CoV-2 antigens such as S and N are still in urgent need, and would provide another test highly complementary to viral RNA detection.
The sixth question concerns how COVID-19 should be treated and what treatment options should be made available. COVID-19 is a self-limiting disease in more than 80% of patients. Severe pneumonia occurred in about 15% of cases as revealed in studies with large cohorts of patients. The gross case fatality is 3.4% worldwide as of February 25, 2020. This rate is 4.4% for patients in Wuhan, 4.0% for patients in Hubei and 0.92% for patients outside of Hubei. The exceedingly high fatality in Wuhan might be explained by the collapse of hospitals, a large number of undiagnosed patients, suboptimal treatment or a combination of these. Up to date, we still do not have any specific anti-SARS-CoV-2 agents but an anti-Ebola drug, remdesivir, may hold the promise. As a nucleotide analog, remdesivir was shown to be effective in preventing MERS-CoV replication in monkeys. Severity of disease, viral replication, and lung damage were reduced when the drug was administered either before or after infection with MERS-CoV. These results provide the basis for a rapid test of the beneficial effects of remdesivir in COVID-19. Other antiviral agents worthy of further clinical investigations include ribavirin, protease inhibitors lopinavir and ritonavir, interferon α2b, interferon β, chloroquine phosphate, and Arbidol. However, we should also bear in mind the side effects of these antiviral agents. For example, type I interferons including interferon α2b and interferon β are well known for their antiviral activity. Their beneficial effects at an early phase of infection are well expected. However, administration at a later stage carries the risk that they might worsen the cytokine storm and exacerbate inflammation. Notably, steroids have been experimentally used widely in the treatment of SARS and are still preferred by some Chinese physicians in the treatment of COVID-19. It is said to be capable of stopping the cytokine storm and preventing lung fibrosis. However, the window in which steroids might be beneficial to patients with COVID-19 is very narrow. In other words, steroids can only be used when SARS-CoV-2 has already been eliminated by human immune response. Otherwise, SARS-CoV-2 replication will be boosted leading to exacerbation of symptoms, substantial virus shedding, as well as increased risk for nosocomial transmission and secondary infection. In this regard, it will be of interest to determine whether the report of fungal infection in the lungs of some patients in Wuhan might be linked to misuse of steroids. Nevertheless, the screening of new pharmaceuticals, small-molecule compounds and other agents that have potent anti-SARS-CoV-2 effects will successfully derive new and better lead compounds and agents that might prove useful in the treatment of COVID-19.
The seventh question is whether inactivated vaccines are a viable option for SARS-CoV-2. The chance that SARS-CoV-2 will become endemic in some areas or even pandemic has increased in view of its high transmissibility, asymptomatic and presymptomatic virus shedding, high number of patients with mild symptoms, as well as the evidence for superspreading events. Thus, vaccine development becomes necessary for prevention and ultimate eradication of SARS-CoV-2. Inactivated vaccines are one major type of conventional vaccines that could be easily produced and quickly developed. In this approach, SARS-CoV-2 virions can be chemically and/or physically inactivated to elicit neutralizing antibodies. In the case of SARS-CoV and MERS-CoV, neutralizing antibodies were successfully and robustly induced by an inactivated vaccine in all types of animal experiments, but there are concerns about antibody-dependent enhancement of viral infection and other safety issues. While inactivated vaccines should still be tested, alternative approaches include live attenuated vaccines, subunit vaccines and vectored vaccines. All of these merit further investigations and tests in animals.
The eighth question relates to the origins of SARS-CoV-2 and COVID-19. To make a long story short, two parental viruses of SARS-CoV-2 have now been identified. The first one is bat coronavirus RaTG13 found in Rhinolophus affinis from Yunnan Province and it shares 96.2% overall genome sequence identity with SARS-CoV-2. However, RaTG13 might not be the immediate ancestor of SARS-CoV-2 because it is not predicted to use the same ACE2 receptor used by SARS-CoV-2 due to sequence divergence in the receptor-binding domain sharing 89% identity in amino acid sequence with that of SARS-CoV-2. The second one is a group of betacoronaviruses found in the endangered species of small mammals known as pangolins, which are often consumed as a source of meat in southern China. They share about 90% overall nucleotide sequence identity with SARS-CoV-2 but carries a receptor-binding domain predicted to interact with ACE2 and sharing 97.4% identity in amino acid sequence with that of SARS-CoV-2. They are closely related to both SARS-CoV-2 and RaTG13, but apparently they are unlikely the immediate ancestor of SARS-CoV-2 in view of the sequence divergence over the whole genome. Many hypotheses involving recombination, convergence and adaptation have been put forward to suggest a probable evolutionary pathway for SARS-CoV-2, but none is supported by direct evidence. The jury is still out as to what animals might serve as reservoir and intermediate hosts of SARS-CoV-2. Although Huanan seafood wholesale market was suggested as the original source of SARS-CoV-2 and COVID-19, there is evidence for the involvement of other wild animal markets in Wuhan. In addition, the possibility for a human superspreader in the Huanan market has not been excluded. Further investigations are required to shed light on the origins of SARS-CoV-2 and COVID-19.
The ninth question concerns why SARS-CoV-2 is less pathogenic. If the reduced pathogenicity of SARS-CoV-2 is the result of adaptation to humans, it will be of great importance to identify the molecular basis of this adaptation. The induction of a cytokine storm is the root cause of pathogenic inflammation both in SARS and COVID-19. SARS-CoV is known to be exceedingly potent in the suppression of antiviral immunity and the activation of proinflammatory response. It is therefore intriguing to see how SARS-CoV-2 might be different from SARS-CoV in interferon-antagonizing and inflammasome-activating properties. It is noteworthy that some interferon antagonists and inflammasome activators encoded by SARS-CoV are not conserved in SARS-CoV-2. Particularly, ORF3 and ORF8 in SARS-CoV-2 are highly divergent from ORF3a and ORF8b in SARS-CoV that are known to induce NLRP3 inflammasome activation. ORF3 of SARS-CoV-2 is also significantly different from the interferon antagonist ORF3b of SARS-CoV. Thus, these viral proteins of SARS-CoV and SARS-CoV-2 should be compared for their abilities to modulate antiviral and proinflammatory responses. The hypothesis that SARS-CoV-2 might be less efficient in the suppression of antiviral response and the activation of NLRP3 inflammasome should be tested experimentally.
Much progress has been made in the surveillance and control of infectious diseases in China after the outbreak of SARS-CoV in 2003. Meanwhile, virological research in the country has also been strengthened. The new disease report and surveillance system did function relatively well during the 2009 pandemic of swine flu. New viral pathogens such as avian influenza virus H7N9 and severe-fever-with-thrombocytopenia syndrome bunyavirus have also been discovered in recent years [11, 12], indicating the strength and vigor of Chinese infectious disease surveillance and virological research. However, the ongoing outbreak of SARS-CoV-2 has not only caused significant morbidity and mortality in China, but also revealed major systematic problems in control and prevention of infectious diseases there. Unfortunately, many of the lessons from the 2003 outbreak have not been learned. Importantly, disease control professionals, practicing physicians and scientists are disconnected in the fight against SARS-CoV-2 and COVID-19. In addition, important decisions were not made by experts in the field. Hopefully, these issues will be dealt with swiftly and decisively during and after the outbreak.
Above we have discussed the two possibilities that this outbreak will unfold. If SARS-CoV-2 is not eliminated from humans through quarantine and other measures, it can still be eradicated by vaccination. If it attenuates to become another community-acquired human coronavirus causing mild respiratory tract disease resembling the other four human coronaviruses associated with common cold, it will not be a disaster either. Before SARS-CoV-2 attenuates further to a much less virulent form, early diagnosis and improved treatment of severe cases hold the key to reduce mortality. We should remain vigilant, but there are grounds for guarded optimism. Redoubling our research efforts on SARS-CoV-2 and COVID-19 will solidify the scientific basis on which important decisions are made.
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.
As an emerging virus, there is no effective drug or vaccine approved for the treatment of SARS-CoV-2 infection yet. Currently, supportive care is provided to the patients, including oxygen therapy, antibiotic treatment, and antifungal treatment, extra-corporeal membrane oxygenation (ECMO) etc. 21,22. To search for an antiviral drug effective in treating SARS-CoV-2 infection, Wang and colleagues evaluated seven drugs, namely, ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine, remdesivir (GS-5734) and favipiravir (T-750) against the infection of SARS-CoV-2 on Vero E6 cells in vitro
63. Among these seven drugs, chloroquine and remdesivir demonstrated the most powerful antiviral activities with low cytotoxicity. The effective concentration (EC50) for chloroquine and remdesivir were 0.77µM and 1.13µM respectively. Chloroquine functions at both viral entry and post-entry stages of the SARS-CoV-2 infection in Vero E6 cells whereas remdesivir does at post-entry stage only. Chloroquine is a drug used for an autoimmune disease and malarial infection with potential broad-spectrum antiviral activities 64,65. An EC90 (6.90 µM) against the SARS-CoV-2 in Vero E6 cells is clinically achievable in vivo according to a previous clinical trial 66. Remdesivir is a drug currently under the development for Ebola virus infection and is effective to a broad range of viruses including SARS-CoV and MERS-CoV 67,68. Functioning as an adenosine analogue targeting RdRp, Remdesivir can result in premature termination during the virus transcription 69,70. The EC90 of remdesivir against SARS-CoV-2 in Vero E6 cells is 1.76 µM, which is achievable in vivo based on a trial in nonhuman primate experiment 63,69. Encouragingly, in the first case of SARS-CoV-2 infection in the United States, treatment with remdesivir was provided intravenously to the patient on the day 7 without any adverse events observed. The patient's clinical condition was improved on day 8 and the previous bilateral lower-lobe rales disappeared, implying the remdesivir might be effective to the treatment of SARS-CoV-2 infection 22. This result, however, should be interpreted with caution as this is only single case study and a proper trial control was lacking. In addition, baricitinib, a Janus kinase inhibitor, was also predicted to reduce the ability of virus to infect lung cell by an analysis of BenevolentAI 71.
Currently, chloroquine and remdesivir are under phase 3 clinical trial and open-label trial for treatment of SARS-CoV-2 infection respectively (Table 2) 72. Preliminary results showed that chloroquine phosphate had apparent efficacy in treatment of COVID-19 73. However, caution must be taken during clinical use of chloroquine as its overdose is highly fatal without known antidote 74. Despite the lack of documented in vitro data supporting the antiviral efficacy on SARS-CoV-2, several antiviral chemotherapeutic agents have been registered for the clinical trials for the treatment of COVID-19 (Table 2) 72.
The detection of SARS-CoV-2 RNA via reverse-transcriptase polymerase chain reaction (RT-PCR) was used as the major criteria for the diagnosis of COVID-19. However, due to the high false-negative rate, which may accelerate the epidemic, clinical manifestations started to be used for diagnosis (which no longer solely relied on RT-PCR) in China on February 13, 2020. A similar situation also occurred with the diagnosis of SARS 59. Therefore, a combination of disease history, clinical manifestations, laboratory tests, and radiological findings is essential and imperative for making an effective diagnosis. On February 14, 2020, the Feng Zhang group described a protocol of using the CRISPR-based SHERLOCK technique to detect SARS-CoV-2, which detects synthetic SARS-CoV-2 RNA fragments at 20 × 10-18 mol/L to 200 × 10-18 mol/L (10-100 copies per microliter of input) using a dipstick in less than an hour without requiring elaborate instrumentation 60. Hopefully, the new technique can dramatically enhance the sensitivity and convenience if verified in clinical samples.
The pre-publication history for this paper can be accessed here:
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.
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).
For ophthalmologists, comprehensive information is needed to understand SARS-CoV-2 feature and epidemiology of the outbreak. Coronaviruses are big, enveloped, single, plus-stranded RNA viruses. Seven coronavirus species are known to cause diseases in humans, among which “severe acute respiratory syndrome coronavirus” (SARS-CoV), “Middle East respiratory syndrome coronavirus”(MERS-CoV), and SARS-CoV-2 drew great attention. SARS-CoV, MERS-CoV and SARS-CoV-2 all belong to the β-CoV family and can cause fatal pneumonia. MERS-CoV carries the highest fatality rate of 34.5%, followed by SARS-CoV (9.6%), then SARS-CoV-2 (3.70%, following data till 12th March 2020), which has a lower disease severity but higher transmission efficiency.
SARS-CoV-2 has been sequenced and was shown to be 75–80% identical to SARS-CoV and 40% identical to MERS-CoV. SARS-CoV-2 shares the same host receptor with SARS-CoV, the human angiotensin-converting enzyme 2 (ACE2) receptor, suggesting a similar transmission route. The person-to-person transmission of SARS-CoV-2 can occur through respiratory droplet transmission and contact transmission. Airborne aerosol and the fecal-oral transmission route remain to be further confirmed.
Theoretically, transmission through the ocular route is likely for SARS-CoV-2. First, its host receptor ACE2 has been identified on the ocular surface [38, 39]. Second, the ocular surface is an open microenvironment. Through the nasolacrimal duct, the virus may transport to the inferior meatus of the nose. Third, the ocular mucosal immune system is associated with lymphoid tissue in the nasolacrimal duct and nasal cavity.
There have been some studies reporting the presence of SARS-CoV or MERS-CoV in tears or conjunctival sac [41, 42], while negative results in all of included patients were also reported. Several investigations have been conducted to identify whether COVID-19 can be transmitted through the ocular route. Shen and colleagues performed a prospective case series study in 30 COVID-19 patients, finding SARS-CoV-2 in two conjunctival swabs of one patient. Another study by Chen et al. demonstrated that out of 67 patients enrolled, SARS-CoV-2 can be detected in the conjunctival sac of three COVID-19 patients without ocular symptoms. Sun et al. found that among 72 patients confirmed by laboratory diagnosis with SARS-CoV-2 RT-PCR assay, SARS-CoV-2 RNA fragments were found in ocular discharges belonging to one patient. The above studies confirmed that SARS-CoV-2 can exist in tears or the conjunctival sac, but the infection of SARS-CoV-2 through the eyes remains uncertain.
The negative results in the ocular surface may be influenced by viral concentration, sampling time lag, and diagnostic method. The time of exposure to SARS-CoV-2 infected patients is critical because of the higher viral load at the early stage of infection. Improvements in the sensitivity of molecular diagnostic methods are needed in the future. More well-designed trials with large sample sizes are required to ascertain whether the ocular route is indeed a mode of transmission.
Practice social distancing in the registration and waiting areas
Patients should stay at least 1.5 m apart from one another when in registration and waiting area.
b)Limit the number of people in the room
Keeping 1 doctor and 1 patient in 1 room is required except for visually impaired patients, patients with communication/mobility difficulties or parents of small children. The room should be well-ventilated. After each patient’s consultation or treatment, the used instruments such as slit lamp must be disinfected immediately.
c)Reduce outpatient examinations
Operation of many ophthalmic equipment requires close proximity, reducing outpatient examinations helps protect both doctors and patients.
Micro-aerosols can be generated when non-contact tonometry is used. Air-puff ophthalmic equipment like non-contact tonometry should be avoided if unnecessary. It is advised to place the tonometer in a ventilated place, and that the measurement interval between patients should be extended. During the measurement, patients should wear a face mask.
Direct ophthalmoscope examination is not recommended, which can be replaced by slit light lens or fundus photography. Protective shields (better transparent) should be installed on slit lamps and any other equipment used which needs close doctor-patient contact. Both doctor and patient should refrain from bare face-to-face speaking during any examination.
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.
The views presented in this article do not necessarily reflect those of the Food and Drug Administration or United States government.