- Kenneth McIntosh, MD
Kenneth McIntosh, MD
- Professor of Pediatrics
- Harvard Medical School
Coronaviruses are important human and animal pathogens. 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, and their possible role in central nervous diseases has been suggested but not proven.
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".)
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) [1,2].
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) . 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 .
- 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.
- International Committee on Taxonomy of Viruses. http://ictvonline.org/virusTaxonomy.asp (Accessed on May 21, 2015).
- Lai MMC, Perlman S, Anderson LJ. Coronaviridae. In: Fields Virology, 5th ed, Knipe DM, Howley PM, Griffin DE, et al (Eds), Lippincott Williams & Wilkins, Philadelphia 2007. p.1305.
- McIntosh K, Peiris JSM. Coronaviruses. In: Clinical Virology, 3rd ed, Richman DD, Whitley RJ, Hayden FG (Eds), ASM Press, Washington, DC 2009. p.1155.
- Enjuanes L, Smerdou C, Castilla J, et al. Development of protection against coronavirus induced diseases. A review. Adv Exp Med Biol 1995; 380:197.
- Masters PS, Kuo L, Ye R, et al. Genetic and molecular biological analysis of protein-protein interactions in coronavirus assembly. Adv Exp Med Biol 2006; 581:163.
- Kuo L, Masters PS. Genetic evidence for a structural interaction between the carboxy termini of the membrane and nucleocapsid proteins of mouse hepatitis virus. J Virol 2002; 76:4987.
- Perlman S. Pathogenesis of coronavirus-induced infections. Review of pathological and immunological aspects. Adv Exp Med Biol 1998; 440:503.
- Luytjes W, Bredenbeek PJ, Noten AF, et al. Sequence of mouse hepatitis virus A59 mRNA 2: indications for RNA recombination between coronaviruses and influenza C virus. Virology 1988; 166:415.
- Siu YL, Teoh KT, Lo J, et al. The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles. J Virol 2008; 82:11318.
- Yeager CL, Ashmun RA, Williams RK, et al. Human aminopeptidase N is a receptor for human coronavirus 229E. Nature 1992; 357:420.
- Hofmann H, Pyrc K, van der Hoek L, et al. Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc Natl Acad Sci U S A 2005; 102:7988.
- Vlasak R, Luytjes W, Spaan W, Palese P. Human and bovine coronaviruses recognize sialic acid-containing receptors similar to those of influenza C viruses. Proc Natl Acad Sci U S A 1988; 85:4526.
- Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367:1814.
- Centers for Disease Control and Prevention (CDC). Severe respiratory illness associated with a novel coronavirus--Saudi Arabia and Qatar, 2012. MMWR Morb Mortal Wkly Rep 2012; 61:820.
- Carstens EB. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2009). Arch Virol 2010; 155:133.
- Vijgen L, Keyaerts E, Moës E, et al. Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event. J Virol 2005; 79:1595.
- Hamre D, Procknow JJ. A new virus isolated from the human respiratory tract. Proc Soc Exp Biol Med 1966; 121:190.
- 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 U S A 1967; 57:933.
- Bradburne AF. Antigenic relationships amongst coronaviruses. Arch Gesamte Virusforsch 1970; 31:352.
- Bradburne AF, Bynoe ML, Tyrrell DA. Effects of a "new" human respiratory virus in volunteers. Br Med J 1967; 3:767.
- McIntosh K, Chao RK, Krause HE, et al. Coronavirus infection in acute lower respiratory tract disease of infants. J Infect Dis 1974; 130:502.
- McIntosh K, Kapikian AZ, Turner HC, et al. Seroepidemiologic studies of coronavirus infection in adults and children. Am J Epidemiol 1970; 91:585.
- Monto AS. Medical reviews. Coronaviruses. Yale J Biol Med 1974; 47:234.
- Esper F, Weibel C, Ferguson D, et al. Evidence of a novel human coronavirus that is associated with respiratory tract disease in infants and young children. J Infect Dis 2005; 191:492.
- Fouchier RA, Hartwig NG, Bestebroer TM, et al. A previously undescribed coronavirus associated with respiratory disease in humans. Proc Natl Acad Sci U S A 2004; 101:6212.
- van der Hoek L, Pyrc K, Jebbink MF, et al. Identification of a new human coronavirus. Nat Med 2004; 10:368.
- Woo PC, Lau SK, Chu CM, et al. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol 2005; 79:884.
- Vabret A, Dina J, Gouarin S, et al. Human (non-severe acute respiratory syndrome) coronavirus infections in hospitalised children in France. J Paediatr Child Health 2008; 44:176.
- Gaunt ER, Hardie A, Claas EC, et al. Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method. J Clin Microbiol 2010; 48:2940.
- Reed SE. The behaviour of recent isolates of human respiratory coronavirus in vitro and in volunteers: evidence of heterogeneity among 229E-related strains. J Med Virol 1984; 13:179.
- Gagneur A, Vallet S, Talbot PJ, et al. Outbreaks of human coronavirus in a pediatric and neonatal intensive care unit. Eur J Pediatr 2008; 167:1427.
- Falsey AR, Dallal GE, Formica MA, et al. Long-term care facilities: a cornucopia of viral pathogens. J Am Geriatr Soc 2008; 56:1281.
- Bradburne AF, Somerset BA. Coronative antibody tires in sera of healthy adults and experimentally infected volunteers. J Hyg (Lond) 1972; 70:235.
- Chonmaitree T, Revai K, Grady JJ, et al. Viral upper respiratory tract infection and otitis media complication in young children. Clin Infect Dis 2008; 46:815.
- Prill MM, Iwane MK, Edwards KM, et al. Human coronavirus in young children hospitalized for acute respiratory illness and asymptomatic controls. Pediatr Infect Dis J 2012; 31:235.
- Zwaans WA, Mallia P, van Winden ME, Rohde GG. The relevance of respiratory viral infections in the exacerbations of chronic obstructive pulmonary disease—a systematic review. J Clin Virol 2014; 61:181.
- McIntosh K, Ellis EF, Hoffman LS, et al. The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J Pediatr 1973; 82:578.
- Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. BMJ 1993; 307:982.
- Kuypers J, Martin ET, Heugel J, et al. Clinical disease in children associated with newly described coronavirus subtypes. Pediatrics 2007; 119:e70.
- Talbot HK, Shepherd BE, Crowe JE Jr, et al. The pediatric burden of human coronaviruses evaluated for twenty years. Pediatr Infect Dis J 2009; 28:682.
- Sizun J, Soupre D, Legrand MC, et al. Neonatal nosocomial respiratory infection with coronavirus: a prospective study in a neonatal intensive care unit. Acta Paediatr 1995; 84:617.
- van der Hoek L, Sure K, Ihorst G, et al. Croup is associated with the novel coronavirus NL63. PLoS Med 2005; 2:e240.
- Sung JY, Lee HJ, Eun BW, et al. Role of human coronavirus NL63 in hospitalized children with croup. Pediatr Infect Dis J 2010; 29:822.
- Walsh EE, Shin JH, Falsey AR. Clinical impact of human coronaviruses 229E and OC43 infection in diverse adult populations. J Infect Dis 2013; 208:1634.
- Falsey AR, McCann RM, Hall WJ, et al. The "common cold" in frail older persons: impact of rhinovirus and coronavirus in a senior daycare center. J Am Geriatr Soc 1997; 45:706.
- Graat JM, Schouten EG, Heijnen ML, et al. A prospective, community-based study on virologic assessment among elderly people with and without symptoms of acute respiratory infection. J Clin Epidemiol 2003; 56:1218.
- Nicholson KG, Kent J, Hammersley V, Cancio E. Acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective, population based study of disease burden. BMJ 1997; 315:1060.
- Kherad O, Kaiser L, Bridevaux PO, et al. Upper-respiratory viral infection, biomarkers, and COPD exacerbations. Chest 2010; 138:896.
- Garbino J, Inoubli S, Mossdorf E, et al. Respiratory viruses in HIV-infected patients with suspected respiratory opportunistic infection. AIDS 2008; 22:701.
- Pene F, Merlat A, Vabret A, et al. Coronavirus 229E-related pneumonia in immunocompromised patients. Clin Infect Dis 2003; 37:929.
- Simon A, Völz S, Fleischhack G, et al. Human coronavirus OC43 pneumonia in a pediatric cancer patient with down syndrome and acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2007; 29:432.
- Szczawinska-Poplonyk A, Jonczyk-Potoczna K, Breborowicz A, et al. Fatal respiratory distress syndrome due to coronavirus infection in a child with severe combined immunodeficiency. Influenza Other Respir Viruses 2013; 7:634.
- Kumar D, Husain S, Chen MH, et al. A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients. Transplantation 2010; 89:1028.
- Gerna G, Passarani N, Battaglia M, Rondanelli EG. Human enteric coronaviruses: antigenic relatedness to human coronavirus OC43 and possible etiologic role in viral gastroenteritis. J Infect Dis 1985; 151:796.
- Chany C, Moscovici O, Lebon P, Rousset S. Association of coronavirus infection with neonatal necrotizing enterocolitis. Pediatrics 1982; 69:209.
- Jevšnik M, Steyer A, Zrim T, et al. Detection of human coronaviruses in simultaneously collected stool samples and nasopharyngeal swabs from hospitalized children with acute gastroenteritis. Virol J 2013; 10:46.
- Risku M, Lappalainen S, Räsänen S, Vesikari T. Detection of human coronaviruses in children with acute gastroenteritis. J Clin Virol 2010; 48:27.
- Esper F, Ou Z, Huang YT. Human coronaviruses are uncommon in patients with gastrointestinal illness. J Clin Virol 2010; 48:131.
- Houtman JJ, Fleming JO. Pathogenesis of mouse hepatitis virus-induced demyelination. J Neurovirol 1996; 2:361.
- Arbour N, Ekandé S, Côté G, et al. Persistent infection of human oligodendrocytic and neuroglial cell lines by human coronavirus 229E. J Virol 1999; 73:3326.
- Boucher A, Desforges M, Duquette P, Talbot PJ. Long-term human coronavirus-myelin cross-reactive T-cell clones derived from multiple sclerosis patients. Clin Immunol 2007; 123:258.
- Arbour N, Day R, Newcombe J, Talbot PJ. Neuroinvasion by human respiratory coronaviruses. J Virol 2000; 74:8913.
- Esper F, Shapiro ED, Weibel C, et al. Association between a novel human coronavirus and Kawasaki disease. J Infect Dis 2005; 191:499.
- Chang LY, Chiang BL, Kao CL, et al. Lack of association between infection with a novel human coronavirus (HCoV), HCoV-NH, and Kawasaki disease in Taiwan. J Infect Dis 2006; 193:283.
- Dominguez SR, Anderson MS, Glodé MP, et al. Blinded case-control study of the relationship between human coronavirus NL63 and Kawasaki syndrome. J Infect Dis 2006; 194:1697.
- Gerna G, Campanini G, Rovida F, et al. Genetic variability of human coronavirus OC43-, 229E-, and NL63-like strains and their association with lower respiratory tract infections of hospitalized infants and immunocompromised patients. J Med Virol 2006; 78:938.
- Gerna G, Percivalle E, Sarasini A, et al. Human respiratory coronavirus HKU1 versus other coronavirus infections in Italian hospitalised patients. J Clin Virol 2007; 38:244.
- Sizun J, Arbour N, Talbot PJ. Comparison of immunofluorescence with monoclonal antibodies and RT-PCR for the detection of human coronaviruses 229E and OC43 in cell culture. J Virol Methods 1998; 72:145.
- Zlateva KT, Coenjaerts FE, Crusio KM, et al. No novel coronaviruses identified in a large collection of human nasopharyngeal specimens using family-wide CODEHOP-based primers. Arch Virol 2013; 158:251.
- Keyaerts E, Vijgen L, Maes P, et al. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004; 323:264.
- Kono M, Tatsumi K, Imai AM, et al. Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK. Antiviral Res 2008; 77:150.
- Keyaerts E, Li S, Vijgen L, et al. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 2009; 53:3416.
- Wood A, Payne D. The action of three antiseptics/disinfectants against enveloped and non-enveloped viruses. J Hosp Infect 1998; 38:283.
- Vennema H, de Groot RJ, Harbour DA, et al. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. J Virol 1990; 64:1407.