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All of the cases had one thing in common: they suffered from severe respiratory illness which was not due to any of the known viral or bacterial causes. The most common initial symptoms were reported to be fever, cough and shortness of breath. Patients rapidly progressed to severe pneumonia and renal failure. The latter presentation has not been seen in all patients. For examples, none of the cases in the Jordanian cluster had renal failure. The two fatal cases in this cluster, one developed pericarditis and the other had disseminated intravascular coagulation. Coronaviruses predominantly cause mild self-limiting upper respiratory tract infections. The only other human coronavirus that is associated with severe lower respiratory infection is SARS-CoV. However, in contrast to SARS-CoV, this novel coronavirus does not appear to cause diarrhea. Of 12 laboratory confirmed cases, 6 have died and 1 is currently in ICU. This would imply a relatively high mortality rate. However, caution has to be exercised, since we do not know the true prevalence of infection with NCoV. It is possible that in some cases, the virus is associated with mild respiratory tract infection which goes unseen and only those patients who develop severe disease seek medical attention. It is also worth noting that all of laboratory confirmed cases have been adults.
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.
Recently, a novel coronavirus has been identified in patients with severe acute respiratory illness. This new virus, provisionally referred to as novel coronavirus (NCoV) has been fully sequenced and shown to belong to group C β-coronaviruses. The genome, which is just over 30 KB, contains at least 10 predicted open reading frames (ORFs). The genome size, organization and sequence analysis revealed that the NCoV is most closely related to bat coronaviruses BtCoV-HKU4 and BtCoV-HKU5 first isolated in 2006 from bats captured in Hong Kong. The major difference between NCoV and these bat coronaviruses is in the region between the spike and the envelop genes. The NCoV has 5 ORFs while the bat viruses have 4 in this region. The nearest human coronavirus related to NCoV is SARS-CoV. This virus was responsible for the outbreak of severe acute respiratory syndrome in 2002–2003 which resulted in 8,422 cases worldwide with 916 deaths. With a mortality of approximately 11% seen with SARS-CoV infection, the identification of NCoV from patients with similar acute respiratory illness as with SARS-CoV is of a real concern. Coronaviruses are a large family of enveloped, single-stranded RNA viruses that infect a number of different species, including humans. They are usually species specific, however interspecies transmission of coronaviruses can occur. Worryingly, in vitro studies show that NCoV is also capable of infecting cells from different species, including monkeys, humans, bats and pigs. Indeed, NCoV was first isolated using monkey kidney epithelial cell lines, Vero and LLC-MK20, both of which are susceptible to infection and can propagate the virus relatively easily. Prior to the isolation of NCoV, only five coronaviruses, namely 229E, OC43, SARS-CoV, HKU1 and NL63, were known to cause infections in humans. In the absence of any underlying co-morbidities, all of these coronaviruses, except for SARS-CoV, are generally associated with mild upper respiratory tract infections. SARS-CoV has an unusual predilection for infecting cells in the lower respiratory tract. Although NCoV also causes lower respiratory tract infection, the viral receptor appears to be different from that used by SARS-CoV.
Avian coronavirus is the main representative of genus Gammacoronavirus, family Coronaviridae, and order Nidovirales. Within the avian coronavirus group, the infectious bronchitis virus (IBV) is among the most researched. This virus is known to cause an important disease that incurs a high economic loss in the poultry industry despite an ongoing vaccination program. It causes respiratory disease while also affecting the kidneys and reproductive tract through viremia with a severity that differs depending on serotypes. Mutations and recombination have produced a high genetic diversity of the virus. In addition, vaccinations performed in the farm setting can influence the evolution of the virus. Many serotypes of IBV are often not cross-protective. Mismatching between the circulating strain and the administered vaccine may contribute to vaccination failure. Ubiquitous IBV and IBV-like viruses have also been found in species other than chicken, such as in peafowl, guinea fowl, partridge, waterfowl, and teal. This finding strengthens the possibility that IBV may have a wider range of hosts than previously thought. Despite this, data relating to IBV in Indonesia is still limited to poultry. Studies of diseases on endemic species are valuable for the conservation effort, yet are rarely conducted.
The Eclectus parrot (Eclectus roratus) is a sexually dichromatic parrot native to a part of Eastern Indonesia and Northern Australia. It is classified as protected in Indonesia according to Government Decree Number 7, Year 1999 and Constitution Number 5, Year 1990. Visually captivating, with both male and female showing radically different plumage, the Eclectus parrot is naturally talkative and popular as a pet. However, there has been limited information about viral diseases among Eclectus parrots. The latest finding on coronavirus in parrots was in 2006 when a virus distinct from IBV was found in the green-cheeked Amazon parrot. Understanding viral diseases in Eclectus parrots may be beneficial for the conservation effort and may provide additional information about viral diseases in birds.
There is limited information as to whether avian coronaviruses cause diseases in Psittacine birds; therefore, information about the presence of this virus among parrots might be valuable for the conservation effort of endemic birds and the poultry industry, which is robust in Indonesia. This study aimed to determine the presence of and to characterize avian coronavirus isolated from Eclectus parrots reared by an Indonesian local bird breeder.
Coronaviruses (CoVs), a genus of the Coronaviridae family, are positive-stranded RNA viruses. The first human coronavirus (HCoV) appeared in reports in the mid-1960s and was isolated from persons with common cold. Two species were first detected: HCoV-229E and subsequently HCoV-OC43 [1, 2]. Since then, more species were described [3–5].
The HCoV-229E strain was associated with common cold symptoms. Younger children and the elderly were considered more vulnerable to lower respiratory tract infections. Severe lower respiratory tract infection so far has only been described in immunocompromised patients [7, 8]. To our knowledge, there is no report describing life-threatening conditions in immunocompetent adults attributed to HCoV-229E. We report a case of acute respiratory distress syndrome developed in a healthy adult with no comorbidities and HCoV-229E strain identified as the only causative agent.
According to the “Diagnosis & Treatment Scheme for Novel Coronavirus Pneumonia (Trial) 6th Edition” enacted by the National Health Commission of the People’s Republic of China on 19 February 2020, the incubation time after exposure is about 1–14 days. Fever, fatigue, and a dry cough are the main manifestations. Nasal obstruction, runny nose, and other upper respiratory symptoms are rare. About half of the patients developed dyspnea one week later, and severe cases developed rapidly into acute respiratory distress syndrome, septic shock, hard-to-correct metabolic acidosis, and coagulation dysfunction. Severe and critical patients may present moderate to low fever, or even no obvious fever. Some patients have mild onset symptoms, no fever, and mostly recovered after one week. Most patients have a favorable prognosis, although some patients are left in a critical condition, or do not survive. The aged patients and the patients with basic diseases have worse prognosis. Children cases are relatively mild.
Acute infections of the respiratory tract are a major cause of morbidity and mortality in humans worldwide and approximately 80% are caused by viruses. The viruses most frequently associated with respiratory tract infections include respiratory syncytial virus (RSV), parainfluenza viruses (PIV), influenza viruses (Flu), adenoviruses (AdV), human rhinoviruses (hRV), and enteroviruses, and less commonly, human metapneumovirus (hMPV), human bocavirus (HBoV), and human coronaviruses (HCoV). Until recently, it was believed that HCoVs were responsible for the common cold syndrome and were the cause of only mild upper respiratory tract infections (URTIs). After the SARS epidemic in 2003, it was established that these viruses can also be associated with severe, life-threatening, or even fatal respiratory infections. Stewart at al. have also suggested a possible relationship between HCoV infections and the development of extrarespiratory symptoms, including some involving the central nervous system. The role of HCoV in human gastrointestinal infections also awaits more detailed exploration.
The aim of this study was to estimate the prevalence of HCoV in a series of hospitalized infants and young children with symptoms of respiratory tract disease at the University Children’s Hospital in Ljubljana from June 2007 to May 2008. The main focus of the present study was to detect all four human coronaviruses in hospitalized children. A proportion of the patients included in this study have been partially described in a separate publication.
The unconfirmed cases met the criteria of the suspected cases and are identified positive with SARS-CoV-2 RNA, by real-time RT-PCR or gene sequencing, from the sputum, throat swab, lower respiratory tract secretion, or other samples collected from patients.
Coronaviruses are positive-sense, single-stranded RNA viruses found in humans and a wide variety of animals. In humans, coronaviruses are mainly causes of respiratory tract infections, whereas in animals, they can cause respiratory, enteric, hepatic and neurological diseases of varying severity. As in other RNA viruses, the infidelity of RNA-dependent RNA polymerase results in high mutation rates. In addition, coronaviruses possess a unique mechanism of viral replication that leads to high frequencies of recombination, as well as the largest genome size (26.4 to 31.7 kb) among all known RNA viruses that gives this family of viruses extra plasticity. All these factors have allowed the coronaviruses to adapt to new hosts and ecological niches. Traditionally, coronaviruses were classified into groups 1, 2 and 3, with groups 1 and 2 consisting of mammalian coronaviruses and group 3 being avian coronaviruses. In 2008, the Coronavirus Study Group of the International Committee for Taxonomy of Viruses proposed three genera, Alphacoronavirus, Betacoronavirus and Gamma-coronavirus, to replace these three traditional groups of coronaviruses (http://talk.ictvonline.org/cfs-filesystemfile.ashx/__key/CommunityServer.Components.PostAttachments/00.00.00.06.26/2008.085_2D00_122V.01.Coronaviridae.pdf).
The SARS epidemic that originated from southern China in 2003 has boosted interest in all areas of coronavirus research, most notably, coronavirus biodiversity and genomics. Before 2003, there were only 10 coronaviruses with complete genomes available, including only two human coronaviruses, human coronavirus 229E (HCoV-229E) and human coronavirus OC43 (HCoV-OC43). These two human coronaviruses were discovered in the 1960s, with HCoV-229E being a group 1 coronavirus and HCoV-OC43 a group 2 coronavirus [17, 34]. After the SARS epidemic, up to December 2008, 16 novel coronaviruses were discovered and their complete genomes sequenced. Among these 16 previously unrecognized coronaviruses were two more human coronaviruses, human coronavirus NL63 (HCoV-NL63) and human coronavirus HKU1 (HCoV-HKU1), ten other mammalian coronaviruses and four avian coronaviruses. HCoV-NL63 is a group 1 coronavirus whereas HCoV-HKU1 is a group 2 coronavirus. In just a few years after their discoveries, numerous reports throughout the world had described the presence of HCoV-NL63 and HCoV-HKU1 in patients with respiratory infections in their corresponding countries. In this article, we reviewed our current understanding of the classification, virology, epidemiology, clinical diseases, laboratory diagnosis, treatment and prevention of HCoV-HKU1.
A 45-year-old female patient presented to the emergency department with dry cough, headache, and fever up to 39.5°C lasting a few hours. Her past medical history was unremarkable, and she did not take any medication regularly. She has never smoked, worked as a teacher at a local high school, and has not recently travelled.
Clinical examination revealed rales at her left lower lung fields. Chest X-ray showed diffuse opacities and consolidation at this field. The arterial blood gases (ABGs) were normal, and intravenous ceftriaxone and azithromycin were empirically administered for lower respiratory tract infection (LRTI). S. pneumoniae and L. pneumophila antigen in the patient's urine specimen was negative, and blood cultures were sterile.
Over the next two days, the patient's clinical condition rapidly deteriorated, with development of tachypnea (34 respirations/minute), dyspnea, and hypoxemia. ABGs changed to PaO2 of 55.3 mmHg, PCO2 of 31.4 mmHg, and pH of 7.487. Lung auscultation revealed diffuse rhonchi symmetrically all over her chest, bronchial breathing at her right and left lower lobes, and diminished vesicular sounds. Chest CT scan displayed bibasilar pleural effusions and diffuse consolidations plus ground glass opacities involving all lung fields (Figure 1). Oxygen was supplied at 5 L/min, and antimicrobial therapy was changed to levofloxacin 500 mg/day. Systemic corticosteroids and bronchodilators were added about 40 hours after her hospitalization. Samples of the pleural fluid showed exudate with 260 cells/mm3, negative Gram stain, and sterile cultures.
Nasal secretions were collected, and multiplex PCR technology was applied targeting multiple pathogens (RespiFinder® 22, PathoFinder), including coronavirus 229E; coronavirus NL63, HKU1, and OC43; influenza A, B, and H1N1; parainfluenza 1, 2, 3, and 4; Mycoplasma pneumoniae; Legionella pneumophila; Bordetella pertussis; bocavirus; rhinovirus/Enterovirus; adenovirus; RSV A and B; and Chlamydophila pneumoniae. The result was positive for HCoV-229E, while negative for the other tested pathogens; PCR for SARS-CoV and MERS-CoV was also negative.
Within the next few hours, the patient's clinical condition further worsened and she required increased oxygen supply. New ABGs showed PaO2 = 76 mmHg, PCO2 = 33 mmHg, and pH = 7.45 at FiO2 = 0.50 with PaO2/FiO2 = 152, indicating ARDS. The patient was in severe respiratory distress and remained febrile and tachypneic, and a new chest X-ray showed multiple consolidations all over her lung fields (Figure 2). Intravenous linezolid was added to her regimen empirically in order to treat a possible community-acquired Staphylococcus aureus pneumonia.
A repeat one-step RT-PCR in a nasal sample (Taqman, in-house protocol, Hellenic Pasteur Institute) confirmed the exclusive presence of human coronavirus 229E (HuCoV-229E). After the administration of systemic corticosteroids, the patient started to display clinical improvement within the first 24 hours. Further laboratory analyses did not reveal any immune defect. After a week, she was discharged from the hospital well and remained healthy 23 months later (Figure 3).
Similar to other human coronaviruses, HCoV-HKU1 is associated with both upper and lower respiratory tract infections. Respiratory tract infections associated with HCoV-HKU1 are indistinguishable from those associated with other respiratory viruses. For upper respiratory tract infections, most patients present with fever, running nose and cough; while for lower respiratory tract infections, fever, productive cough and dyspnea are common presenting symptoms. Most HCoVHKU1 infections are self-limiting, with only two deaths reported in patients with HCoV-HKU1 pneumonia. Both had underlying diabetes mellitus, cardiovascular diseases (myocardial infarction in one and cerebrovascular accident in the other) and cancers (gastric lymphoma in one and prostatic carcinoma in the other), lymphopenia and airspace shadows in both lungs. Interestingly, a recent study from rural Thailand that involved control patients showed the presence of human coronaviruses in >2% of control patients, which raised questions about the role of human coronaviruses in pneumonia. At the moment, no antiviral drugs or vaccines for HCoV-HKU1 and the other human coronaviruses are available. Symptomatic and supportive treatment is the mainstay of therapy given to patients suffering from infections caused by these viruses.
In addition to respiratory tract infections, HCoV-HKU1 has been found in other illnesses. In our one-year prospective study, it was observed that HCoV-HKU1 infection was associated with febrile seizures. On the other hand, in another French study, although six (17.6%) of the 34 HCoV-HKU1 infected children were admitted for epileptic seizures, HCoV-HKU1 infections were not shown to be associated with febrile seizures. In one study, HCoV-HKU1 was detected in the stool samples of two patients with respiratory tract infections but no gastrointestinal tract symptoms, but it was not detected in patients with diarrhea. In another study, HCoV-HKU1 was detected in a liver transplant recipient with hepatitis, which other causes of hepatitis, such as graft rejection, cytomegalovirus, etc. were excluded. The significance of HCoV-HKU1 febrile seizures, gastroenteritis and hepatitis remains to be determined.
From June 2007 to May 2008, 897 respiratory specimens from 741 pediatric patients hospitalized at the University Children’s Hospital in Ljubljana with acute respiratory tract infections (ARTIs), were sent to the laboratory of the Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, for the routine detection of respiratory viruses. The number of patients included in this study represented virtually all of hospitalized children with diagnosis of viral respiratory tract infection in this period.
Of these, 664 (74%) respiratory specimens (nasopharyngeal and throat swabs in viral transport medium, tracheal aspirates, bronchoalveolar lavage, or sputum) from 592 preschool children aged from three days to 72 months were included in to further analysis. Each of the 664 samples represented a different hospitalization event, except for one child from whom two different samples were taken and submitted for analysis (nasopharyngeal swab and bronchoalveolar lavage). Remaining 233 (26%) respiratory specimens were collected from 149 children either older than 72 months or were taken during the same hospitalization event. Therefore these specimens were excluded from the further analysis.
Demographic and clinical data were extracted from the children’s medical records and were available for 37 HCoV-positive children and 395 HCoV-negative children.
The present study was approved by the National Medical Ethics Committee, Ljubljana, Slovenia (no. 60/02/09).
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),,,.
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 %).
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.
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.
Canine enteric coronavirus (CCoV) is a common infection of dogs, particularly those housed in large groups such as kennels, shelters, and breeding facilities. CCoV belongs to the family Coronaviridae, order Nidovirales, and was first recognized as a pathogen of dogs following virus isolation of the prototype 1-71 virus in 1971 during an outbreak of gastroenteritis in military dogs. Classically, CCoV was considered to cause only self-limiting enteritis with mild diarrheal disease. However, CCoV has emerged as a significant pathogen in veterinary medicine, and is increasingly found to be an important cause of disease. The viral spike protein binds the host cell receptor and triggers fusion of the viral and cellular membranes. As such, it is an important determinant of cell tropism and pathogenicity. Based on the high level of naturally occurring recombinations and mutations among coronaviruses, especially within the spike gene, there is the likelihood of continued emergence of novel CCoVs with distinct pathogenic properties in the future.
Coronaviruses (CoVs) are well-known causes of severe infections, respiratory, enteric and systemic, in humans and numerous animal hosts. The CoV infections have been reported in cattle, swine, horses, camels, rodents, cats, dogs, bats, palm civets, ferrets, mink, rabbits, snake, and several other wild animals and avian species (Fehr and Perlman 2015; Kahn and McIntosh 2005). The coronaviruses of relevant veterinary species are shown in Table 1 with organ affected and clinical signs. Though human CoVs were identified for the first time in the year 1960 from respiratory infections in adults as well as children, the major scientific interest in CoVs research grew only after the emergence of Severe Acute Respiratory Syndrome CoV (SARS-CoV) in the year 2002-2003 (Drosten et al. 2003; Ksiazek et al. 2003; Peiris et al. 2003). In this SARS-CoV epidemic, around 8000 confirmed human cases with 774 deaths (around 9.5% mortality rate) occurred that was a result of its global spread (Kahn and McIntosh 2005). Initially, the virus was detected in the caged Himalayan palm civets and these were thought to be the natural host of this virus (Guan et al. 2003). Following SARS-CoV incidence in 2003, a similar CoV named HKU3-1 to HKU3-3 were identified in the horseshoe bats (non-caged) in 2005 from Hong Kong (Lau et al. 2005). Since then, bats are considered to be the natural host and potential reservoir species that could be held responsible for any future CoVs epidemics and/or pandemics (Cui et al. 2019, Li et al. 2005). After the 2003 and 2005 SARS-CoV epidemics, an analogous virus emerged in the Middle East region of the world leading to severe respiratory illness and was named the Middle East Respiratory Syndrome CoV (MERS-CoV) (Zaki et al. 2012). The mortality was higher than previous SARS-CoV pandemic claiming around 919 lives out of the total 2521 human cases (around 35% mortality) (World Health Organization 2015). Notably, dromedary camels were connected with the transmission of MERS-CoV (Alagaili et al. 2014). Further, its origin was also traced from bats (Ithete et al. 2013). All these highly pathogenic human CoVs, SARS and MERS, show emergence over wider areas of the world posing high risk of human-to-human transmission and fatal consequences thereto (Figure 1).
This decade’s first CoV emergency was from Hubei province of China, and as on February 4, 2020, 425 deaths have been reported in China only (World Health Organization 2020b). Further, the spread of this novel coronavirus, named 2019-nCoV, has been noted in 24 countries till date. Considering the global threat of the 2019-nCoV, the World Health Organization (WHO) declared it as a ‘Public Health Emergency of International Concern’ on January 30th, 2020.
This rapid communication provides an overview of the recently emerging coronavirus (2019-nCoV) with regards to its current scenario, comparative analysis with respects to previously reported CoVs, evolutionary perspective based on genome analysis while covering the recent advances on vaccines and therapeutics in brief.
The 2019 novel coronavirus pneumonia is caused by a novel betacoronavirus that is currently named 2019 novel coronavirus, which was identified by deep sequencing analysis from lower respiratory tract samples [1, 2]. The 2019 novel coronavirus is the seventh member of enveloped RNA coronavirus that can infect humans. On one hand most human coronavirus infections are mild, on the other hand the infections of coronavirus including 2019 novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-COV) could be severe or even deadly.
In early December 2019, the first patient with 2019 novel coronavirus pneumonia emrged in Wuhan city, Hubei province, China. Subsequently the 2019 novel coronavirus pneumonia rapidly spread throughout china. Soon afterwards many countries declared the first case of 2019 novel coronavirus pneumonia [4–8]. The 2019 novel coronavirus pneumonia emerged in more than 151 countries, and the number of laboratory-confirmed cases reached 167,511 and that of the death cases was 6606 in the world as of March 16th, 2020 according to the information from the official website of World Health Organization.
In the past 2 months several studies have described the clinical characteristics of patients with 2019 novel coronavirus pneumonia [2, 9, 10]. However some cases in these studies had one or more chronic or severe underlying diseases, which made it difficult to fully assess the role of 2019 novel coronavirus in 2019 novel coronavirus pneumonia without too much interference. Thus we excluded cases with chronic or severe underlying diseases (i.e., chronic lung disease, chronic heart disease, chronic liver disease, chronic kidney disease) from our study and analysed the data on 95 patients with 2019 novel coronavirus pneumonia.
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.
Coronavirus, the members of Coronaviridae family are the diverse group of virus which infects domestic animals, birds as well as human. Coronaviruses are enveloped RNA viruses which are classified into four genera, Alpha coronavirus, Beta coronavirus, Gamma coronavirus and Delta coronavirus. HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HCoV-HKU1 and MERS-CoV are the six types of human coronaviruses evolved in between 1960 and 2015 whereas MERS-CoV is newly emerged strain. This newly emerged MERS-CoV, which is highly fatal, belongs to lineage C of the genus Beta coronavirus. Human coronaviruses have been tracked down to zoonotic origin. Among the six strains of human corona-viruses, the first HCoV-229E has structural similarity with Bat coronaviruses. This phenomenon resemble to other members that are also have originated from different animal corona-virus like HCoV-OC43 from bovine corona-virus, SARS-CoV and HCoV-NL63 from bat or palm civet corona-virus and HCoV-HKU1 from Mouse hepatitis virus (MHV). Like other human coronaviruses, it is assumed that MERS-CoV has been evolved from zoonotic origin but the zoonotic source of MERS-CoV remains unknown [3–5].
Some studies identified some close amino acid similarity between MERS-CoV and Nycteris and Pipistrellus bat species. But recent reports identified that MERS-CoV is more closely related to Tylonycteris bat CoV HKU4 (Ty-BatCoV HKU4) and Pipistrellus bat CoV HKU5 (Pi-BatCoV HKU5). MERS-CoV and Bat-CoV HKU5 bat corona-viruses shared high degree of amino acid similarity in their RNA polymerase (92.1 to 92.3 %), 3C-like protease (82 %), polymerase (92 %), and proofreading exonuclease (91 %) and nucleocapsid (N) protein (68 %) [8, 9]. But it is more closely related to Ty-BatCoV HKU4 in S and N. The major difference between MERS-CoV and these bat corona-viruses is in the region between the spike and the envelop genes. The MERS-CoV has five ORFs while the bat viruses have four in this region [3–5, 10].
Though the MERS-CoV is structurally related to the bat-CoV but there is no report of the sharing of antigenic sites among those corona-viruses. To better understand the evolutionary origin of MERS-CoV pathogenicity it is really needed to know in which extent they are conserved in their immunogenicity.
In this study, we identify the conserved antigenic site among MERS and Bat Corona-virus. For this, bioinformatics analyses of their spike (S), membrane (M), enveloped (E) and nucleocapsid (N) proteins were done for finding the conserved antigenic sites and for mapping the evolutionary conserved antigenic sites on their 3D structures which were determined by threading modeling technique.
Coronaviruses cause a spectrum of illness from asymptomatic disease to respiratory failure. Early reports of coronavirus infections suggested that most infections were mild until the 2003 SARS epidemic that was associated with significant morbidity and mortality. In September 2012, a novel coronavirus was identified in a 60-year old man in Saudi Arabia. A second case was identified in a Qatari patient hospitalized in the United Kingdom. The two coronaviruses were genetically identical and similar to isolates obtained from bats. In July 2013, the coronavirus study group named this new virus Middle East respiratory syndrome coronavirus (MERS–CoV).
As of December 21, 2015, there have been 1625 cases worldwide with 586 deaths. The epidemiology and clinical manifestations of this disease have described a spectrum of illness from asymptomatic infection to severe respiratory failure and death. The overall mortality rate remains at 37 % [7–15]. Importantly, there are no known effective treatments. In 2014 there was an increase in MERS-CoV cases reported from the Jeddah region of Saudi Arabia. To describe the changing epidemiology and outcomes, we report the clinical features and treatment outcomes of patients admitted to a regional referral hospital in Jeddah, Saudi Arabia.
King Fahd General Hospital is an 800-bed hospital in Jeddah, Kingdom of Saudi Arabia and is a regional coronavirus referral center. There are 36 ICU beds and one Infectious Disease physician that serves the hospital. Between January through December 2014, all patients admitted or transferred to King Fahd Hospital with a positive MERS coronavirus PCR from clinical nasal swabs or nasopharyngeal aspirates were included.
Amplification was performed on original swab samples and allantoic fluids. None of these samples was positive for the 3’-UTR of the avian coronavirus (UTR11−/41+). Three out of 10 swab samples were positive for the N gene coronavirus, but none of them was positive for the S1 IBV gene. However, four out of 10 samples of allantoic fluid tested were positive for the coronavirus N gene. Of the two that tested positive for the S1 gene of IBV, only one of them, which was designated as parrot/Indonesia/BX9/16, was able to be further sequenced. These results are presented in Table-3.
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.