Published on 22/03/2015 by admin
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Chapter 256 Coronaviruses
Mark R. Denison
Coronaviruses are increasingly recognized as important pathogens of humans. They cause up to 15% of common colds and are implicated as causes of croup, asthma exacerbations, and lower respiratory tract infections, including bronchiolitis and pneumonia. In addition there is evidence that coronaviruses may be causes of enteritis or colitis in neonates and infants and may be underappreciated as agents of meningitis or encephalitis. The discovery that severe acute respiratory syndrome (SARS) is caused by a novel human coronavirus (SARS-CoV) has led to increased surveillance and the recognition of additional human coronaviruses, revealing that new coronaviruses enter human populations from zoonotic vectors such as bats.
Coronaviruses are enveloped viruses of medium to large size (80-220 nm) that possess the largest known single-stranded positive-sense RNA genomes. Coronaviruses derive their name from the characteristic surface projections of spike protein, which give a corona or crownlike appearance on negative-stain electron microscopy. Traditionally coronaviruses have been organized taxonomically into 3 groups (1-3) on the basis of antigenic relationships. This has been changed to a lettering system based on genomic phylogenetic relationships. Group 1 coronaviruses (alpha—α) includes human coronavirus 229E (HCoV-229E) and the recently identified HCoV-NL63; group 2 (beta—β) includes HCoV-OC43 and the recently discovered HCoV-HKU1; and group 3 (gamma—γ) includes avian coronaviruses but no known human viruses. The SARS epidemic resulted in discovery of a vast number of additional coronaviruses in bats and other mammals, resulting in new genus and species designations. Non-SARS human diseases are associated principally with HCoVs OC43, 229E, NL63, and HKU1.
Coronavirus infections have a worldwide distribution. Past seroprevalence studies demonstrated that that seropositivity to 229E and OC43 increases rapidly during early childhood so that by early adulthood, 90-100% of persons are seropositive. Although less information is available for HKU1 and NL63, available studies demonstrate similar patterns of seroconversion to these viruses during early childhood. Although some degree of strain-specific protection may be afforded by recent infection, re-infections are common and have been noted to occur despite the presence of strain-specific antibody. Attack rates are similar in different age groups. Although infections occur throughout the year, there is a peak during the winter and early spring for each of the HCoVs. In the USA, outbreaks of OC43 and 229E have occurred in 2- to 3-yr alternating cycles. Independent studies of viral etiologies of upper and lower respiratory infections (URIs and LRIs) during the same period but from different locations and countries have confirmed that all known human coronaviruses have a worldwide distribution. Both previous culture and PCR multiplex studies have demonstrated that coronaviruses often occur as co-infections with other respiratory viruses, including respiratory syncytial virus (RSV), adenovirus, rhinovirus (RV), or human metapneumovirus (HMPV).
Volunteer studies demonstrated that OC43 and 229E are transmitted predominantly through the respiratory route. Droplet spread appears to be most important, although aerosol transmission may also play a role. Coronaviruses have been reported to cause minimal cytopathology. Studies with SARS-CoV in human airway epithelial cell cultures indicate that ciliated cells are principal targets for infection and that infected ciliated cells may be directly extruded or lost from the infected monolayer. Thus it may be that cytopathology of other human respiratory coronaviruses is manifested as individual cell infection and loss. The amount of pathology due to direct cell damage is not well-defined, but infection with OC43 and 229E is associated with the elaboration of cytokines, including interleukin-8 (IL-8) and interferon-γ (IFN-γ), suggesting that symptoms may be at least partially due to the host immune response. In experimentally infected volunteers, serum-specific immunoglobulin (Ig) A and IgG antibody levels peak 12-14 days after infection but decline rapidly thereafter. At 1 yr following experimental infection there is only partial protection against re-infection with the homologous strain.
Human coronaviruses OC43 and 229E have been conclusively demonstrated in human volunteer studies to cause respiratory disease, with these viruses and newly identified NL63 and HKU1 strongly implicated in colds, bronchiolitis, pneumonia, and croup. The possible role of human coronaviruses in gastrointestinal and neurologic disease is less well-defined and remains to be proven.
Up to 50% of respiratory tract infections with OC43 and 229E may be asymptomatic. Coronaviruses account for up to 15% of common colds. Cold symptoms caused by human coronaviruses are indistinguishable from those caused by rhinoviruses and other respiratory viruses. The average incubation period is 2-4 days, with symptoms typically lasting 4-7 days. Rhinorrhea, cough, sore throat, malaise, and headache are the most common symptoms. Fever may be more common than previously thought, occurring in up to 60% of cases. Coronavirus NL63 is implicated as a cause of croup in children <3 yr of age. Coronavirus infections have been linked to episodes of wheezing in asthmatic children, albeit at a lower frequency and severity than observed with rhinovirus and respiratory syncytial virus infections. Lower respiratory tract infections, including bronchiolitis and pneumonia, have also been reported in immunocompetent as well as immunocompromised children and adults. HCoV-HKU1 was originally identified in two adults with pneumonia. As with RSV or RV, coronavirus detection in URIs frequently may be associated with acute otitis media and isolation from middle ear fluid.
Although the precise role of coronaviruses in human gastrointestinal disease remains controversial, there is some evidence to support such a role, particularly in young children. Coronavirus-like particles have been detected by electron microscopy in the stools of infants with nonbacterial gastroenteritis. In addition, several outbreaks in neonatal intensive care units of gastrointestinal disease characterized by diarrhea, bloody stools, abdominal distention, bilious gastric aspirates, and classic necrotizing enterocolitis have also been associated with the presence of coronavirus-like particles in stools. In older children and adults, coronavirus-like viruses have been observed with similar frequency in symptomatic and asymptomatic individuals.
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