Coronaviruses - UpToDate

1/29/2020 Coronaviruses - UpToDate
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Coronaviruses
Author: Kenneth McIntosh, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2019. | This topic last updated: Jan 28, 2020.
INTRODUCTION
Coronaviruses are important human and animal pathogens. During epidemics, they are the cause of up to one-third of
community-acquired upper respiratory tract infections in adults and probably also play a role in severe respiratory
infections in both children and adults. In addition, it is possible that certain coronaviruses cause diarrhea in infants and
children. Their role in central nervous system diseases, except for a single case report of encephalitis in a severely
immunocompromised infant, has been suggested but not proven. (See 'Neurologic disease' below.)
The microbiology, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of community-acquired
coronaviruses will be discussed here. Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East
respiratory syndrome coronavirus (MERS-CoV) are reviewed separately. (See "Severe acute respiratory syndrome
(SARS)" and "Middle East respiratory syndrome coronavirus: Virology, pathogenesis, and epidemiology".)
NOVEL CORONAVIRUS (2019-NCOV) OUTBREAK IN CHINA
Epidemiology — A novel coronavirus, designated 2019-nCoV, was identified as the cause of a cluster of pneumonia
cases in Wuhan, a city in the Hubei province of China, at the end of 2019. By late January 2020, thousands of
laboratory-confirmed cases in China had been reported, and the case count has been rising daily; the majority of reports
are from the Hubei province, but numerous cases have been reported in other provinces and municipalities in China,
including Beijing [1,2]. Sporadic cases among travelers from Wuhan have also been reported in other countries globally
(including nearby countries in Asia, as well as Australia, France, Germany, the United States [Washington state, Illinois,
California, and Arizona], and Canada) [3-6]. Updated case counts in English can be found on the World Health
Organization and the European Centre for Disease Prevention and Control websites.
Epidemiologic investigation in Wuhan identified an association with a seafood market where most patients had worked
or visited and which was subsequently closed for disinfection [7]. The seafood market also sold live rabbits, snakes, and
other animals. However, many laboratory-confirmed cases had no contact with this market, and cases have been
reported among health care workers. Human-to-human transmission has been confirmed in China and has also been
identified in other countries.
Virology — Full-genome sequencing and phylogenic analysis indicated that 2019-nCoV is a betacoronavirus, in a
distinct clade from the betacoronaviruses associated with human severe acute respiratory syndrome (SARS) and Middle
East respiratory syndrome (MERS) [8]. It has close similarity to bat coronaviruses, and it is likely that bats are the
primary source, but whether 2019-nCoV is transmitted directly from bats or through some other mechanism (eg, through
an intermediate host) is unknown [9]. (See 'Viral serotypes' below.)
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Clinical features — The illness is characterized primarily by fever, cough, dyspnea, and bilateral infiltrates on chest
imaging [1,2,7,10]. The incubation period of 2019-nCoV is thought to be within 14 days following exposure. Although
many of the reported infections are not severe, approximately 20 percent of confirmed patients have had critical illness
(including respiratory failure, septic shock, or other organ failure requiring intensive care). Most of the fatal cases have
occurred in patients with underlying medical comorbidities.
In a study describing 41 of the initial cases identified in the outbreak, 73 percent of cases were males, and the median
age was 49 (interquartile range 41 to 58 years) [10]. Nearly all (98 percent) reported fever, 76 percent had cough, and
44 percent had myalgias/fatigue. Dyspnea developed in 55 percent after a median of eight days of illness. Lymphopenia
was common and all patients had parenchymal lung abnormalities on computed tomography (CT) of the chest, including
ground glass opacities, subsegmental consolidation, and multilobular consolidation. Acute respiratory distress syndrome
developed in 30 percent, and mechanical ventilation was implemented in 10 percent.
In a family cluster of infections, the onset of fever and respiratory symptoms occurred approximately three to six days
after presumptive exposure [11].
Clinical suspicion, evaluation, diagnosis, and management — The possibility of 2019-nCoV should be considered in
patients with fever and/or lower respiratory tract symptoms who reside in or have recently (within the prior 14 days)
traveled to the Wuhan area of China or who have had recent close contact with a confirmed or suspected case of 2019-
nCoV.
When 2019-nCoV is suspected, infection control measures should be implemented and public health officials notified. In
the United States, the Centers for Disease Control and Prevention (CDC) recommends a cautious approach to infection
control in the clinical setting and advises standard, contact, and airborne precautions as well as eye protection [12]. In
addition to testing for other respiratory pathogens, the CDC recommends collection of specimens from the lower
respiratory tract (sputum, tracheal aspirate, or bronchoalveolar lavage), upper respiratory tract
(nasopharyngeal/oropharyngeal swab or nasopharyngeal wash), and serum.
2019-nCoV is detected by polymerase chain reaction; in the United States, testing is performed by the CDC.
Management of documented cases consists of supportive care.
Understanding of this novel coronavirus is evolving rapidly. The World Health Organization (WHO) has issued interim
guidance on surveillance case definitions, laboratory diagnosis, and clinical management. The CDC has also issued
interim guidance.
Links to these and other related society guidelines are found elsewhere. (See 'Society guideline links' below.)
Global public health measures — WHO guidance highlights general measures to reduce transmission of infection,
including diligent hand and respiratory hygiene, and avoiding close contact with live or dead animals and sick
individuals. It does not recommend international travel restrictions but does advise exit screening for international
travelers from areas with ongoing transmission of 2019-nCoV to identify individuals with fever, cough, or potential high-
risk exposure [13].
In China, health officials announced a restriction of public transportation within and a halt of air and rail traffic out of
Wuhan and other surrounding areas [1]. In the United States, the CDC recommends that individuals avoid all
nonessential travel to China [14]; airports in some major cities (including San Francisco, Los Angeles, and New York
City) had begun screening air travelers from Wuhan for signs of illness on arrival.
VIROLOGY
Coronaviruses are classified as a family within the Nidovirales order, viruses that replicate using a nested set of mRNAs
("nido-" for "nest"). The coronavirus subfamily is further classified into four genera: alpha, beta, gamma, and delta
coronaviruses. The human coronaviruses (HCoVs) are in two of these genera: alpha coronaviruses (HCoV-229E and
HCoV-NL63) and beta coronaviruses (HCoV-HKU1, HCoV-OC43, Middle East respiratory syndrome coronavirus
[MERS-CoV], and the severe acute respiratory syndrome coronavirus [SARS-CoV]) (figure 1) [15,16].
Viral composition — Coronaviruses are medium-sized enveloped positive-stranded RNA viruses whose name derives
from their characteristic crown-like appearance in electron micrographs (picture 1) [17,18]. These viruses have the
largest known viral RNA genomes, with a length of 27 to 32 kb. The host-derived membrane is studded with glycoprotein
spikes and surrounds the genome, which is encased in a nucleocapsid that is helical in its relaxed form but assumes a
roughly spherical shape in the virus particle (figure 2). Replication of viral RNA occurs in the host cytoplasm by a unique
mechanism in which RNA polymerase binds to a leader sequence and then detaches and reattaches at multiple
locations, allowing for the production of a nested set of mRNA molecules with common 3' ends (figure 3).
The genome encodes four or five structural proteins, S, M, N, HE, and E. HCoV-229E, HCoV-NL63, and the SARS
coronavirus possess four genes that encode the S, M, N, and E proteins, respectively, whereas HCoV-OC43 and HCoV-
HKU1 also contain a fifth gene that encodes the HE protein [19].
● The spike (S) protein projects through the viral envelope and forms the characteristic spikes in the coronavirus
"crown." It is heavily glycosylated, probably forms a homotrimer, and mediates receptor binding and fusion with the
host cell membrane. The major antigens that stimulate neutralizing antibody, as well as important targets of
cytotoxic lymphocytes, are on the S protein [20]. Receptor usage is discussed below. (See 'Viral serotypes' below.)
● The membrane (M) protein has a short N-terminal domain that projects on the external surface of the envelope and
spans the envelope three times, leaving a long C terminus inside the envelope. The M protein plays an important
role in viral assembly [21].
● The nucleocapsid protein (N) associates with the RNA genome to form the nucleocapsid. It may be involved in the
regulation of viral RNA synthesis and may interact with M protein during virus budding [21,22]. Cytotoxic T
lymphocytes recognizing portions of the N protein have been identified [23].
● The hemagglutinin-esterase glycoprotein (HE) is found only in the betacoronaviruses, HCoV-OC43 and HKU1 (see
'Viral serotypes' below). The hemagglutinin moiety binds to neuraminic acid on the host cell surface, possibly
permitting initial adsorption of the virus to the membrane. The esterase cleaves acetyl groups from neuraminic acid.
The HE genes of coronaviruses have sequence homology with influenza C HE glycoprotein and may reflect an
early recombination between the two viruses [24].
● The small envelope (E) protein leaves its C terminus inside the envelope and then either spans the envelope or
bends around and projects its N terminus internally. Its function is not known, although, in the SARS-CoV, the E
protein along with M and N are required for proper assembly and release of the virus [25].
Viral serotypes — Coronaviruses are widespread among birds and mammals, with bats being host to the largest
variety of genotypes [26]. Animal and human coronaviruses fall into four distinct genera (figure 1) [15,16]. There are five
non-SARS coronavirus serotypes that have been associated with disease in humans: HCoV-229E, HCoV-NL63, HCoV-
OC43, HCoV-HKU1, and a novel coronavirus (MERS-CoV) that emerged in 2012.
● The alphacoronavirus genus includes two human virus species, HCoV-229E and HCoV-NL63. HCoV-229E, like
several animal alphacoronaviruses, utilizes aminopeptidase N (APN) as its major receptor [27]. In contrast, HCoV-
NL63, like the SARS-CoV (a betacoronavirus), uses angiotensin-converting enzyme-2 (ACE-2) [28]. Important
animal alphacoronaviruses are transmissible gastroenteritis virus of pigs and feline infectious peritonitis virus. There
are also several related bat coronaviruses among the alphacoronaviruses.
● Two of the non-SARS human species of the betacoronavirus genus, HCoV-OC43 and HCoV-HKU1, have
hemagglutinin-esterase activity and probably utilize sialic acid residues as receptors [29]. This genus also contains
several bat viruses, MERS-CoV [30,31], and SARS-CoV, although the last two are genetically somewhat distant
from HCoV-OC43 and HCoV-HKU1 (figure 1).
Important animal betacoronaviruses are mouse hepatitis virus, a laboratory model for both viral hepatitis and
demyelinating central nervous system disease, and bovine coronavirus, a diarrhea-causing virus of cattle. Bovine
coronavirus is so similar to HCoV-OC43 that the two viruses have been merged into a single species termed
betacoronavirus 1 [32]. HCoV-OC43 is thought to have jumped from one animal host to the other as recently as
1900 [33].
● The gammacoronavirus genus contains primarily avian coronaviruses, the most prominent of which is infectious
bronchitis virus of chickens. This is an important veterinary pathogen causing respiratory and reproductive tract
disease in chickens.
● The deltacoronavirus genus contains recently discovered avian coronaviruses found in several species of
songbirds.
None of the community-acquired human coronaviruses (HCoV-OC43, HCoV-NE63, HCoV-HKU1, and HCoV-229E)
replicate easily in tissue culture, and, until recently, this impeded progress in their study. Both HCoV-229E and HCoV-
OC43 were discovered in the 1960s and were shown in volunteer experiments to produce common colds in adults
[17,34-36]. Studies in the 1970s and 1980s linked them to as much as one-third of upper respiratory tract infections
during winter outbreaks, 5 to 10 percent of overall colds in adults, and some proportion of lower respiratory illness in
children [37-39].
Little further information developed after this until the emergence of SARS in 2002 and the development of molecular
diagnostic methods. Then HCoV-NL63 and HCoV-HKU1 were quickly discovered and found to have worldwide
distribution [40-43]. The polymerase chain reaction may be used for the diagnosis of each of the four human
coronaviruses, and this technique has allowed substantial investigation into their epidemiology and pathogenicity. (See
'Diagnosis' below.)
EPIDEMIOLOGY
Seasonality — Community-acquired coronaviruses are ubiquitous; wherever investigators have looked, they have been
detected. In temperate climates, coronavirus respiratory infections occur primarily in the winter, although smaller peaks
are sometimes seen in the fall or spring, and infections can occur at any time of the year [38,44,45]. A seven-year study
of hospitalized children in Guangzhou, China, described the seasonality in a subtropical region, with outbreaks at almost
any time of year but predominantly in the spring and fall [46]. In other surveys, HCoV-OC43, HCoV-NL63, HCoV-229E,
and HCoV-HKU1 predominate unpredictably in certain years and in certain parts of the world [39,45-47]. In almost all
such surveys, HCoV-OC43 is the most common of the four strains, followed by HCoV-NL63, but the prevalence of the
various strains in any particular year is often unpredictable.
A large polymerase chain reaction (PCR)-based study of viruses in adults and children with acute respiratory illness was
performed in Scotland, with sampling in over 44,000 episodes over nine years and gives some idea of the incidence and
seasonality of community-acquired HCoV infections in relation to other respiratory viruses in a temperate climate [48].
HCoV infections were most common in the winter, were distributed across all age groups, and were less common than
those caused by rhinovirus, influenza, or respiratory syncytial virus but more common than other respiratory viruses;
coinfections were relatively common, particularly in young children.
A nine-year survey of all children under 16 years of age admitted for acute respiratory illness at the only hospital in Sør-
Trøndelag County, Norway, a region with approximately 59,000 children, found that both HCoV-OC43 and HCoV-NL63
were detected most frequently and were epidemic every other winter, that HCoV-HKU-1 usually prevailed every other
winter during the years when HCoV-OC43 and HCoV-NL63 did not, and that detection of 229E was unusual [47]. HCoV-
associated lower respiratory tract infection hospitalization rates for the population under five years were calculated at 1.5
per 1000 children per year.
Routes of transmission — Respiratory coronaviruses probably spread in a fashion similar to that of rhinoviruses, via
direct contact with infected secretions or large aerosol droplets. Immunity develops soon after infection but wanes
gradually over time. Reinfection is common, presumably because of waning immunity, but possibly because of antigenic
variation within species [49]. In hospital settings, spread among pediatric patients probably occurs through shedding by
their infected caretakers [50]. Outbreaks are common in long-term care facilities for older adults [51].
Middle East respiratory syndrome and severe acute respiratory syndrome are both zoonoses. Animals implicated in
these infections are discussed in detail separately. (See "Middle East respiratory syndrome coronavirus: Virology,
pathogenesis, and epidemiology", section on 'Possible sources and modes of transmission' and "Severe acute
respiratory syndrome (SARS)", section on 'Intermediate host and reservoir'.)
CLINICAL MANIFESTATIONS
The clinical manifestations of infections caused by community-acquired human coronaviruses (HCoVs) are described
here; Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus
(SARS-CoV) are discussed separately. (See "Severe acute respiratory syndrome (SARS)", section on 'Clinical
manifestations' and "Middle East respiratory syndrome coronavirus: Clinical manifestations and diagnosis", section on
'Clinical manifestations'.)
Respiratory — HCoV-229E and HCoV-OC43 have been proven to have pathogenicity in humans in volunteer studies
where they, along with other less well-characterized coronavirus strains, reproducibly induced colds very similar to those
induced by rhinoviruses, characterized by upper respiratory tract symptoms such as nasal congestion and rhinorrhea
[36,52]. It is assumed that HCoV-NL63 and HCoV-HKU1 have similar pathogenicity, but proof of this is lacking.
Moreover, when tested by polymerase chain reaction (PCR), asymptomatic individuals of all ages periodically carry
coronaviruses.
Human coronaviruses probably account for 5 to 10 percent of all acute upper respiratory tract infections in adults [39],
with outbreaks during which 25 to 35 percent of respiratory infections can be attributed to a single species. Like
rhinoviruses, coronaviruses can be detected in middle ear effusions and have been implicated as important viral causes
of acute otitis media in children [53]. Respiratory tract infection surveys that include asymptomatic babies and children
indicate that coronaviruses, like rhinoviruses, are often coinfections with other respiratory viruses and are also often
found in the absence of respiratory symptoms, suggesting that, although common, their pathogenicity in healthy infants
and children may be low [47,54]. In one large study, when the concentration of viral RNA found in nasopharyngeal
aspirates was measured (using the PCR cycle threshold value), multivariate analysis showed a significant association
between a high HCoV RNA concentration (cycle threshold <28) and both respiratory tract disease (compared with
asymptomatic controls) and lack of coinfection [47]. (See "Epidemiology, clinical manifestations, and pathogenesis of
rhinovirus infections" and "Acute otitis media in children: Epidemiology, microbiology, clinical manifestations, and
complications", section on 'Viral pathogens'.)
Coronavirus infections have also been linked to more severe respiratory diseases. In adults with community-acquired
pneumonia, coronaviruses are detected by PCR at frequencies similar to or somewhat lower than those of other
respiratory viruses such as influenza virus, rhinovirus, and respiratory syncytial virus. Their etiologic role is not clear, in
part because copathogens are often found. In three studies, simultaneous sampling of healthy adults was carried out. In
one study, coronaviruses were detected more frequently in those with pneumonia (13 percent) than in healthy controls
(4 percent), although coronaviruses were also detected in a substantial proportion of patients with nonpneumonic lower
respiratory tract infection (10 percent) [55]. In a third study, which included 3104 adults in Europe spanning two and a
half years, patients with lower respiratory tract infection (which included community-acquired pneumonia as well as
cough without evidence of pneumonia) were sampled [56]. HCoV was the third most common virus detected (after
rhinovirus and influenza virus) and was found significantly more often than in matched healthy controls. In another study,
the numbers were small and the difference in detection of coronaviruses in adults with community-acquired pneumonia
compared with asymptomatic individuals was not significant [57].
The ratio of HCoV-OC43 outpatient infections to inpatient infections was threefold lower than that for HCoV-229E,
suggesting that HCoV-OC43 may have greater clinical impact. Another survey of severe acute respiratory infections
from 2010 to 2014 in Arizona in the United States found influenza virus most frequently (50 cases), followed by human
metapneumovirus (25 cases), parainfluenza viruses (20 cases), coronaviruses (16 cases), and respiratory syncytial
virus (11 cases); among coronaviruses, HCoV-OC43 predominated [58]. Further information on the role of coronaviruses
in acute respiratory illness in adults comes from a four-year cohort study comparing HCoV-229E with HCoV-OC43 [59].
Among older adult patients, there is increasing evidence that coronaviruses are important causes of influenza-like
illness, acute exacerbations of chronic bronchitis, and pneumonia, where their frequency is below those of influenza and
respiratory syncytial virus but similar to that of rhinoviruses [60-63]. Several outbreaks of HCoV-OC43 respiratory
disease in older adults living in long-term care facilities have been described [64,65], with case-fatality rates of 8
percent. A fatal case of acute respiratory distress syndrome in a 76-year-old woman with no underlying diseases and
mono-infection with HCoV-NL63 has also been reported [66].
In children hospitalized in New York City with HCoV infection and respiratory disease, a majority were under five years
of age and had some underlying condition such as heart disease, chronic lung disease, or congenital abnormalities [67].
Coronaviruses have been found in 4 to 6 percent of adults with exacerbations of chronic obstructive pulmonary disease
(less frequent than rhinoviruses and respiratory syncytial virus; equally frequent or somewhat less frequent than
influenza; and more frequent than parainfluenza viruses, human metapneumovirus, and adenoviruses) [68]. They have
been temporally linked to acute asthma attacks in both children and adults [69-71]. They have been found in variable
proportions, ranging from 2 to 8 percent, of neonates, infants, and young children hospitalized with community-acquired
pneumonia, and have been identified even more frequently in lower respiratory tract disease in outpatients [37,72,73].
They are also an important cause of nosocomial infections in neonatal intensive care units [74]. One of the more
recently discovered human coronaviruses, HCoV-NL63, has been associated with croup in children [67,75,76].
Coronaviruses also probably cause pneumonia in immunocompromised hosts, including adults with HIV infection [77-
80]. Twenty-eight HCoV-infected hematopoietic cell transplant (HCT) recipients were compared with published series of
similar HCT patients with influenza virus, RSV, and parainfluenza virus infections from the same center [81]. All viruses
were detected in bronchoalveolar lavage specimens. In multivariable models, no differences in survival were seen
between the HCoV-infected patients and those infected with the other respiratory viruses. There is also some evidence
of an association between coronavirus infection and acute rejection and bronchiolitis obliterans syndrome in lung
transplant recipients, although the association is less clear than for other respiratory viruses [82]. (See "Parainfluenza
viruses in adults" and "Parainfluenza viruses in children" and "Viral infections following lung transplantation", section on
'Rejection'.)
The clinical manifestations of MERS-CoV and SARS-CoV are discussed separately. (See "Severe acute respiratory
syndrome (SARS)", section on 'Clinical manifestations' and "Middle East respiratory syndrome coronavirus: Clinical
manifestations and diagnosis", section on 'Clinical manifestations'.)
Enteric — The idea that coronaviruses produce diarrhea in humans is intriguing because of their clear intestinal
pathogenicity in animals. Early human studies depended on finding "coronavirus-like particles" (CVLPs) by electron
microscopy in stool samples. The most convincing studies showed a strong association between the presence of CVLPs
and diarrhea in infants [83] or necrotizing enterocolitis in newborns [84]. In several studies, CVLPs have been purified
that appear to be antigenically related to HCoV-OC43 [83].
All four HCoV species have been found by reverse-transcriptase polymerase chain reaction (RT-PCR) in the stools of a
small proportion of infants and children hospitalized with diarrhea (often with respiratory symptoms as well) [44,85].
Three surveys of diarrhea used molecular methods to screen for all four HCoV species known to cause community-
acquired infections. In one study, all four species were found in stools from 2.5 percent of 878 children with diarrhea and
1.8 percent of 112 asymptomatic children by RT-PCR; however, in this and other surveys, most diarrhea-associated
coronavirus-positive stools also contained other known pathogens, such as rotavirus or norovirus [85,86]. In a study that
used RT-PCR to investigate the frequency of coronaviruses in stool samples from children and adults with
gastrointestinal illness, CoV-HKU1 was found in 4 of 479 patients (0.8 percent), and no other HCoV species were found
[87].
A study assessed the association between gastrointestinal manifestations (diarrhea, vomiting, nausea, and abdominal
pain) in adults reporting to general practitioners with respiratory symptoms plus systemic symptoms or signs (fever,
chills, headache, or myalgia) [88]. Viruses were sought from respiratory and stool samples and bacteria from stool
samples only. Gastrointestinal symptoms, which occurred in 57 percent of patients, were more likely to occur in those
with fever >39°C (102.2°F), headache, a gastrointestinal pathogen, or HCoV respiratory infection. Although a few
HCoVs were found in stool samples, the authors thought that these were likely swallowed viruses. The pathogenetic
mechanism of these gastrointestinal manifestations remains unclear.
POSSIBLE DISEASE ASSOCIATIONS
Neurologic disease — The clear involvement of several animal coronaviruses in acute and chronic neurologic disease
has stimulated a search for similar pathogenicity of human coronaviruses. Community-acquired human coronaviruses
(HCoVs) can infect neural cells in vitro [89], and three-week-old mice develop generalized encephalitis after
intracerebral inoculation with HCoV-OC43 [90]. HCoV-OC43 RNA sequences have been detected in the cerebrospinal
fluid of a 15-year-old boy with acute demyelinating encephalomyelitis (ADEM) [91]. In another report, full-length HCoV-
OC43 RNA was recovered from the brain, with widespread cerebral immunohistochemical staining at autopsy, in an 11-
month-old boy with severe combined immunodeficiency and acute encephalitis following umbilical cord blood
transplantation [92].
With the observation that rats and mice infected with certain strains of mouse hepatitis virus (MHV) developed a severe
demyelinating encephalitis similar to multiple sclerosis (MS) [93], investigators have sought to link coronaviruses with
MS. Currently available evidence is inconclusive. T cell clones from patients with MS have been shown to react both
with HCoV-229E antigens and myelin basic protein, suggesting molecular mimicry as a basis of pathogenesis [94].
Some, but not all, investigators have detected RNA of the human coronaviruses, HCoV-OC43 and HCoV-229E, more
frequently in brain tissue from MS patients by reverse-transcriptase polymerase chain reaction than in healthy
individuals [95].
Despite these findings, an etiologic connection between coronaviruses and MS or other demyelinating diseases remains
tentative and unproven. (See "Manifestations of multiple sclerosis in adults".)
Kawasaki disease — An association of coronavirus infection with Kawasaki disease was reported by one group of
investigators and stimulated a flurry of investigation worldwide [96]. Others failed to confirm this finding, and, at the
present time, it is assumed that known coronaviruses have no role in this disease [97,98]. (See "Kawasaki disease:
Epidemiology and etiology", section on 'Infectious etiology'.)
DIAGNOSIS
Since there is no effective treatment for coronavirus infections, establishing the diagnosis is of limited utility in patients
suspected of having community-acquired coronavirus infections. In contrast, diagnosing Middle East respiratory
syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) is critically
important for understanding outbreak epidemiology and limiting transmission of infection. (See "Severe acute respiratory
syndrome (SARS)", section on 'Diagnosis' and "Middle East respiratory syndrome coronavirus: Clinical manifestations
and diagnosis", section on 'Diagnosis'.)
Until recently, no sensitive, rapid method existed to detect all of the known human coronavirus strains. Rapid techniques
that can be used to detect coronaviruses from nasopharyngeal samples include reverse-transcriptase polymerase chain
reaction (RT-PCR) and immunofluorescence antigen detection assays [99-101].
Because of its utility for detecting all four of the known human coronavirus strains to cause community-acquired
infections, RT-PCR has supplanted other diagnostic methods. Although broadly reacting pan-coronavirus primers have
been developed, they are less sensitive than primers designed for each of the four human strains [99,102]. The
sensitivity may be further improved by using real-time RT-PCR [45]. (See "Severe acute respiratory syndrome (SARS)",
section on 'Diagnosis'.)
Community-acquired coronaviruses are difficult to replicate in tissue culture.
TREATMENT AND PREVENTION
There is currently no treatment recommended for coronavirus infections except for supportive care as needed. Several
antivirals and other agents were used during the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak,
but the efficacy of these drugs has not been established. (See "Severe acute respiratory syndrome (SARS)", section on
'Treatment'.)
Chloroquine, which has potent antiviral activity against the SARS-CoV [103], has been shown to have similar activity
against HCoV-229E in cultured cells [104] and against HCoV-OC43 both in cultured cells and in a mouse model [105].
However, there have been no studies of efficacy in humans.
Preventive measures are the same as for rhinovirus infections, which consist of handwashing and the careful disposal of
materials infected with nasal secretions. Several antiseptic/disinfectant solutions used commonly in hospitals and
households, including chloroxylenol, benzalkonium chloride, and cetrimide/chlorhexidine, have been shown to be
ineffective against coronaviruses [106].
There has been little interest in developing vaccines for the non-SARS community-acquired coronaviruses for several
reasons. First, four separate species have been described and there is evidence within at least one of these species of
clinically significant antigenic variation [49]. In addition, vaccine enhancement of disease has been shown for one animal
coronavirus, feline coronavirus; hypersensitivity was induced in some animals by prior exposure to a vaccine containing
the S protein, with the production of an immunologically mediated severe disease, feline infectious peritonitis, upon
reinfection with a coronavirus [107]. There has been interest in the development of a SARS-CoV vaccine and a MERS-
CoV vaccine. (See "Severe acute respiratory syndrome (SARS)", section on 'Vaccine development' and "Middle East
respiratory syndrome coronavirus: Treatment and prevention", section on 'Vaccine development'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Novel coronavirus" and "Society guideline links: Middle East
respiratory syndrome coronavirus".)
SUMMARY AND RECOMMENDATIONS
● Coronaviruses are the cause of 5 to 10 percent of community-acquired upper respiratory tract infections in adults,
occurring sporadically or in outbreaks of variable size, and probably also play a role in severe respiratory infections
in both children and adults, particularly adults with underlying pulmonary disease and older adults. (See
'Introduction' above and 'Clinical manifestations' above.)
● Coronaviruses are medium-sized enveloped positive-stranded RNA viruses whose name derives from their
characteristic crown-like appearance in electron micrographs (picture 1). (See 'Viral composition' above.)
● Community-acquired coronaviruses are ubiquitous; wherever investigators have looked, they have been detected.
In temperate climates, coronavirus respiratory infections occur primarily in the winter, although smaller peaks are
sometimes seen in the fall or spring, and infections can occur at any time of the year. (See 'Epidemiology' above.)
● Most community-acquired coronavirus infections are diagnosed clinically, although reverse-transcriptase

polymerase chain reaction applied to respiratory secretions is the diagnostic test of choice. (See 'Diagnosis' above
and "Middle East respiratory syndrome coronavirus: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
● There is currently no treatment recommended for coronavirus infections except for supportive care as needed. (See
'Treatment and prevention' above and "Middle East respiratory syndrome coronavirus: Treatment and prevention",
section on 'Treatment'.)
● Severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus are discussed in
detail separately. (See "Severe acute respiratory syndrome (SARS)" and "Middle East respiratory syndrome
coronavirus: Virology, pathogenesis, and epidemiology".)
● In late 2019, a novel coronavirus, designated 2019-nCoV, was identified as the cause of an outbreak of acute
respiratory illness that has included thousands of cases in China and scattered cases worldwide. The possibility of
2019-nCoV should be considered in patients with fever and/or lower respiratory tract symptoms who reside in or
have recently (within 14 days) traveled to the Wuhan area of China or who have had recent close contact with a
confirmed or suspected case of 2019-nCoV. (See 'Novel coronavirus (2019-nCoV) outbreak in China' above.)
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Topic 8298 Version 40.0
GRAPHICS
Coronavirus phylogenetic tree
Phylogenetic tree of 50 coronaviruses with partial nucleotide sequences of RNA-dependent RNA polymerase. The tree was constructed by the
neighbor-joining method using MEGA 5.0. The scale bar indicates the estimated number of substitutions per 20 nucleotides.
AntelopeCoV: sable antelope coronavirus; BCoV: bovine coronavirus; BdCoV HKU22: bottlenose dolphin coronavirus HKU22; BuCoV HKU11: bulbul
coronavirus HKU11; BWCoV-SW1: beluga whale coronavirus SW1; CMCoV HKU21: common-moorhen coronavirus HKU21; DcCoV UAE-HKU23: dromedary
camel coronavirus UAE-HKU23; ECoV: equine coronavirus; Erinaceous-CoV: betacoronavirus Erinaceus/VMC/DEU/2012; FIPV: feline infectious peritonitis
virus; HCoV-229E: human coronavirus 229E; HCoV-HKU1: human coronavirus HKU1; HCoV-NL63: human coronavirus NL63; HCoV-OC43: human
coronavirus OC43; Hi-BatCoV HKU10: Hipposideros bat coronavirus HKU10; IBV-partridge: avian infectious bronchitis virus partridge isolate; IBV-peafowl:
avian infectious bronchitis virus peafowl isolate; KSA-CAMEL-363: KSA-CAMEL-363 isolate of Middle East respiratory syndrome coronavirus; MERS-CoV:
Middle East respiratory syndrome coronavirus; MHV: murine hepatitis virus; Mi-BatCoV 1A: Miniopterus bat coronavirus 1A; Mi-BatCoV 1B: Miniopterus bat
coronavirus 1B; Mi-BatCoV HKU7: Miniopterus bat coronavirus HKU7; Mi-BatCoV HKU8: Miniopterus bat coronavirus HKU8; MRCoV HKU18: magpie robin
coronavirus HKU18; MunCoV HKU13: munia coronavirus HKU13; My-BatCoV HKU6: Myotis bat coronavirus HKU6; NeoCoV: coronavirus Neoromicia/PML-
PHE1/RSA/2011; NHCoV HKU19: night heron coronavirus HKU19; PEDV: porcine epidemic diarrhea virus; PHEV: porcine hemagglutinating
encephalomyelitis virus; Pi-BatCoV-HKU5: Pipistrellus bat coronavirus HKU5; PorCoV HKU15: porcine coronavirus HKU15; PRCV: porcine respiratory
coronavirus; RbCoV HKU14: rabbit coronavirus HKU14; RCoV parker: rat coronavirus Parker; Rh-BatCoV HKU2: Rhinolophus bat coronavirus HKU2; Ro-
BatCoV-HKU9: Rousettus bat coronavirus HKU9; Ro-BatCoV HKU10: Rousettus bat coronavirus HKU10; SARSCoV: severe acute respiratory
syndrome coronavirus; SARSr-CiCoV: SARS-related palm civet coronavirus; SARSr-Rh-BatCoV HKU3: SARS-related Rhinolophus bat coronavirus HKU3; Sc-
BatCoV 512: Scotophilus bat coronavirus 512; SpCoV HKU17: sparrow coronavirus HKU17; TCoV: turkey coronavirus; TGEV: transmissible gastroenteritis
virus; ThCoV HKU12: thrush coronavirus HKU12; Ty-BatCoV-HKU4: Tylonycteris bat coronavirus HKU4; WECoV HKU16: white-eye coronavirus HKU16;
WiCoV HKU20: wigeon coronavirus HKU20.
From: Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: Another zoonotic betacoronavirus causing SARS-like disease. Clin
Microbiol Rev 2015; 28:465. DOI: 10.1128/CMR.00102-14. Reproduced with permission from American Society for Microbiology. Copyright © 2015.
Graphic 101403 Version 1.0
Coronavirus electron micrograph
Group of coronavirus particles, negatively stained with phosphotungstic acid

(PTA). Some variation in size is seen, but shape is relatively uniform.
Magnification 144,000x.
Reproduced with permission from: McIntosh K, Dees JH, Becker WB, et al. Recovery
in tracheal organ cultures of novel viruses from patients with respiratory disease. Proc
Natl Acad Sci USA. 1967; 57:933. Copyright © 1967 Kenneth McIntosh, MD.
Model of coronavirus structure: A schematic diagram of

virion structure
Schematic showing the major structural proteins of the coronavirus virion.
S: spike protein; M: membrane protein; E: envelope protein; N: nucleocapsid protein.
Reproduced with permission from: Masters PS, Perlman S. Coronaviridae. In: Fields
Virology, 6th edition, Knipe DM, Howley PM (Eds), Lippincott Williams & Wilkins,
Philadelphia, 2013. Copyright © 2013 Lippincott Williams & Wilkins. www.lww.com.
Coronavirus replication
Steps in coronavirus replication that are potential targets for antiviral drugs and vaccines. The spike
glycoprotein S is a good candidate for vaccines because neutralizing antibodies are directed against S.
Blockade of the specific virus receptor on the surface of the host cell by monoclonal antibodies or other
ligands can prevent virus entry. Receptor-induced conformational changes in the S protein can be blocked
by peptides that inhibit membrane fusion and virus entry. The polyprotein of the replicase protein is
cleaved into functional units by virus-encoded proteinases. Protease inhibitors may block replication. The
polymerase functions in a unique membrane-bound complex in the cytoplasm, and the assembly and
functions of this complex are potential drug targets. Viral mRNAs made by discontinuous transcription are
shown in the cytoplasm with the protein that each encodes indicated at the right. The common 70 base
long leader sequence on the 5' end of each mRNA is shown in red. Budding and exocytosis are processes
essential to virus replication that may be targets for development of antiviral drugs.
M: membrane protein required for virus budding; S: viral spike glycoprotein that has receptor binding and
membrane fusion activities; E: small membrane protein that plays a role in coronavirus assembly; N:
nucleocapsid phosphoprotein associated with viral RNA inside the virion.
Reproduced with permission from: Holmes KV. SARS coronavirus: a new challenge for prevention and therapy. J
Clin Invest 2003; 111:1605. Copyright © 2003 American Society for Clinical Investigation.
Contributor Disclosures
Kenneth McIntosh, MD Nothing to disclose Martin S Hirsch, MD Nothing to disclose Allyson Bloom, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately
referenced content is required of all authors and must conform to UpToDate standards of evidence.
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NOVEL CORONAVIRUS (2019-NCOV) OUTBREAK IN CHINA

Management of documented cases consists of supportive care.

POSSIBLE DISEASE ASSOCIATIONS

Community-acquired coronaviruses are difficult to replicate in tissue culture.

TREATMENT AND PREVENTION

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Most community-acquired coronavirus infections are diagnosed clinically, although reverse-transcriptase

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9. Perlman S. Another Decade, Another Coronavirus. N Engl J Med 2020.

14. CDC Travelers' Health. Novel coronavirus in China. https://wwwnc.cdc.gov/travel/notices/warning/novel-coronaviru

16. International Committee on Taxonomy of Viruses. http://ictvonline.org/virusTaxonomy.asp (Accessed on May 21, 2

Topic 8298 Version 40.0

Coronavirus phylogenetic tree

Graphic 101403 Version 1.0

Coronavirus electron micrograph

Group of coronavirus particles, negatively stained with phosphotungstic acid

Graphic 62033 Version 3.0

Model of coronavirus structure: A schematic diagram of

Schematic showing the major structural proteins of the coronavirus virion.

S: spike protein; M: membrane protein; E: envelope protein; N: nucleocapsid protein.

Graphic 53049 Version 13.0

Graphic 74041 Version 3.0

Conflict of interest policy

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