Abstract
Lower respiratory tract infections are the leading cause of death in children worldwide. Studies on the epidemiology and clinical associations of the four human non‐SARS human coronaviruses (HCoVs) using sensitive polymerase chain reaction (PCR) assays are needed to evaluate the clinical significance of HCoV infections worldwide. Pediatric respiratory specimens (1,683) submitted to a diagnostic virology laboratory over a 1‐year period (December 2004–November 2005) that were negative for seven respiratory viruses by conventional methods were tested for RNA of four HCoVs using sensitive RT‐PCR assays. Coronavirus RNAs were detected in 84 (5.0%) specimens: HCoV‐NL63 in 37 specimens, HCoV‐OC43 in 34, HCoV‐229E in 11, and HCoV‐HKU1 in 2. The majority of HCoV infections occurred during winter months, and over 62% were in previously healthy children. Twenty‐six (41%) coronavirus positive patients had evidence of a lower respiratory tract infection (LRTI), 17 (26%) presented with vomiting and/or diarrhea, and 5 (8%) presented with meningoencephalitis or seizures. Respiratory specimens from one immunocompromised patient were persistently positive for HCoV‐229E RNA for 3 months. HCoV‐NL63‐positive patients were nearly twice as likely to be hospitalized (P = 0.02) and to have a LRTI (P = 0.04) than HCoV‐OC43‐positive patients. HCoVs are associated with a small, but significant number (at least 2.4% of total samples submitted), of both upper and lower respiratory tract illnesses in children in Colorado. Our data raise the possibility that HCoV may play a role in gastrointestinal and CNS disease. Additional studies are needed to investigate the potential roles of HCoVs in these diseases. J. Med. Virol. 81:1597–1604, 2009. © 2009 Wiley‐Liss, Inc.
Keywords: coronavirus, rhinovirus, respiratory infection, children
Supporting information
REFERENCES
- Arbour N, Day R, Newcombe J, Talbot PJ. 2000. Neuroinvasion by human respiratory coronaviruses. J Virol 74: 8913–8921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arden KE, Nissen MD, Sloots TP, Mackay IM. 2005. New human coronavirus, HCoV‐NL63, associated with severe lower respiratory tract disease in Australia. J Med Virol 75: 455–462. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bastien N, Robinson JL, Tse A, Lee BE, Hart L, Li Y. 2005. Human coronavirus NL‐63 infections in children: A 1‐year study. J Clin Microbiol 43: 4567–4573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bellau‐Pujol S, Vabret A, Legrand L, Dina J, Gouarin S, Petitjean‐Lecherbonnier J, Pozzetto B, Ginevra C, Freymuth F. 2005. Development of three multiplex RT‐PCR assays for the detection of 12 respiratory RNA viruses. J Virol Methods 126: 53–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Briese T, Renwick N, Venter M, Jarman RG, Ghosh D, Kondgen S, Shrestha SK, Hoegh AM, Casas I, Adjogoua EV, Akoua‐Koffi C, Myint KS, Williams DT, Chidlow G, van den Berg R, Calvo C, Koch O, Palacios G, Kapoor V, Villari J, Dominguez SR, Holmes KV, Harnett G, Smith D, Mackenzie JS, Ellerbrok H, Schweiger B, Schonning K, Chadha MS, Leendertz FH, Mishra AC, Gibbons RV, Holmes EC, Lipkin WI. 2008. Global distribution of novel rhinovirus genotype. Emerg Infect Dis 14: 944–947. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cabirac GF, Soike KF, Zhang JY, Hoel K, Butunoi C, Cai GY, Johnson S, Murray RS. 1994. Entry of coronavirus into primate CNS following peripheral infection. Microb Pathog 16: 349–357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caul EO, Ashley CR, Egglestone SI. 1977. Recognition of human enteric coronaviruses by electron microscopy. Med Lab Sci 34: 259–263. [PubMed] [Google Scholar]
- Chiu SS, Chan KH, Chu KW, Kwan SW, Guan Y, Poon LL, Peiris JS. 2005. Human coronavirus NL63 infection and other coronavirus infections in children hospitalized with acute respiratory disease in Hong Kong, China. Clin Infect Dis 40: 1721–1729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coiras MT, Aguilar JC, Garcia ML, Casas I, Perez‐Brena P. 2004. Simultaneous detection of fourteen respiratory viruses in clinical specimens by two multiplex reverse transcription nested‐PCR assays. J Med Virol 72: 484–495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dare RK, Fry AM, Chittaganpitch M, Sawanpanyalert P, Olsen SJ, Erdman DD. 2007. Human coronavirus infections in rural Thailand: A comprehensive study using real‐time reverse‐transcription polymerase chain reaction assays. J Infect Dis 196: 1321–1328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Souza Luna LK, Heiser V, Regamey N, Panning M, Drexler JF, Mulangu S, Poon L, Baumgarte S, Haijema BJ, Kaiser L, Drosten C. 2007. Generic detection of coronaviruses and differentiation at the prototype strain level by reverse transcription‐PCR and nonfluorescent low‐density microarray. J Clin Microbiol 45: 1049–1052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dominguez SR, Briese T, Palacios G, Hui J, Villari J, Kapoor V, Tokarz R, Glode MP, Anderson MS, Robinson CC, Holmes KV, Lipkin WI. 2008. Multiplex MassTag‐PCR for respiratory pathogens in pediatric nasopharyngeal washes negative by conventional diagnostic testing shows a high prevalence of viruses belonging to a newly recognized rhinovirus clade. J Clin Virol 43: 219–222. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguiere AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Muller S, Rickerts V, Sturmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW. 2003. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 348: 1967–1976. [DOI] [PubMed] [Google Scholar]
- Ebihara T, Endo R, Ma X, Ishiguro N, Kikuta H. 2005. Detection of human coronavirus NL63 in young children with bronchiolitis. J Med Virol 75: 463–465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Esper F, Weibel C, Ferguson D, Landry ML, Kahn JS. 2005. Evidence of a novel human coronavirus that is associated with respiratory tract disease in infants and young children. J Infect Dis 191: 492–498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Esper F, Weibel C, Ferguson D, Landry ML, Kahn JS. 2006. Coronavirus HKU1 infection in the United States. Emerg Infect Dis 12: 775–779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fendrick AM, Monto AS, Nightengale B, Sarnes M. 2003. The economic burden of non‐influenza‐related viral respiratory tract infection in the United States. Arch Intern Med 163: 487–494. [DOI] [PubMed] [Google Scholar]
- Gerna G, Percivalle E, Sarasini A, Campanini G, Piralla A, Rovida F, Genini E, Marchi A, Baldanti F. 2007. Human respiratory coronavirus HKU1 versus other coronavirus infections in Italian hospitalised patients. J Clin Virol 38: 244–250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Glaser CA, Gilliam S, Schnurr D, Forghani B, Honarmand S, Khetsuriani N, Fischer M, Cossen CK, Anderson LJ. 2003. In search of encephalitis etiologies: Diagnostic challenges in the California Encephalitis Project, 1998–2000. Clin Infect Dis 36: 731–742. [DOI] [PubMed] [Google Scholar]
- Griffin MR, Walker FJ, Iwane MK, Weinberg GA, Staat MA, Erdman DD. 2004. Epidemiology of respiratory infections in young children: Insights from the new vaccine surveillance network. Pediatr Infect Dis J 23: S188–S192. [DOI] [PubMed] [Google Scholar]
- Heikkinen T, Jarvinen A. 2003. The common cold. Lancet 361: 51–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heim A, Ebnet C, Harste G, Pring‐Akerblom P. 2003. Rapid and quantitative detection of human adenovirus DNA by real‐time PCR. J Med Virol 70: 228–239. [DOI] [PubMed] [Google Scholar]
- Holmes KV. 2001. Coronaviruses In: Knipe D, editor. Fields' virology, 4th edition Philadelphia: Lippincott Williams and Wilkins; pp 1187–1203. [Google Scholar]
- Houtman JJ, Fleming JO. 1996. Pathogenesis of mouse hepatitis virus‐induced demyelination. J Neurovirol 2: 361–376. [DOI] [PubMed] [Google Scholar]
- Kaiser L, Regamey N, Roiha H, Deffernez C, Frey U. 2005. Human coronavirus NL63 associated with lower respiratory tract symptoms in early life. Pediatr Infect Dis J 24: 1015–1017. [DOI] [PubMed] [Google Scholar]
- Klig JE. 2004. Current challenges in lower respiratory infections in children. Curr Opin Pediatr 16: 107–112. [DOI] [PubMed] [Google Scholar]
- Klig JE, Shah NB. 2005. Office pediatrics: Current issues in lower respiratory infections in children. Curr Opin Pediatr 17: 111–118. [DOI] [PubMed] [Google Scholar]
- Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson LJ. 2003. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 348: 1953–1966. [DOI] [PubMed] [Google Scholar]
- Kusel MM, de Klerk NH, Holt PG, Kebadze T, Johnston SL, Sly PD. 2006. Role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life: A birth cohort study. Pediatr Infect Dis J 25: 680–686. [DOI] [PubMed] [Google Scholar]
- Kuypers J, Martin ET, Heugel J, Wright N, Morrow R, Englund JA. 2007. Clinical disease in children associated with newly described coronavirus subtypes. Pediatrics 119: e70–e76. [DOI] [PubMed] [Google Scholar]
- Lau SK, Woo PC, Yip CC, Tse H, Tsoi HW, Cheng VC, Lee P, Tang BS, Cheung CH, Lee RA, So LY, Lau YL, Chan KH, Yuen KY. 2006. Coronavirus HKU1 and other coronavirus infections in Hong Kong. J Clin Microbiol 44: 2063–2071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lau SK, Yip CC, Tsoi HW, Lee RA, So LY, Lau YL, Chan KH, Woo PC, Yuen KY. 2007. Clinical features and complete genome characterization of a distinct human rhinovirus (HRV) genetic cluster, probably representing a previously undetected HRV species, HRV‐C, associated with acute respiratory illness in children. J Clin Microbiol 45: 3655–3664. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leung WK, To KF, Chan PK, Chan HL, Wu AK, Lee N, Yuen KY, Sung JJ. 2003. Enteric involvement of severe acute respiratory syndrome‐associated coronavirus infection. Gastroenterology 125: 1011–1017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lu X, Chittaganpitch M, Olsen SJ, Mackay IM, Sloots TP, Fry AM, Erdman DD. 2006. Real‐time PCR assays for detection of bocavirus in human specimens. J Clin Microbiol 44: 3231–3235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maertzdorf J, Wang CK, Brown JB, Quinto JD, Chu M, de Graaf M, van den Hoogen BG, Spaete R, Osterhaus AD, Fouchier RA. 2004. Real‐time reverse transcriptase PCR assay for detection of human metapneumoviruses from all known genetic lineages. J Clin Microbiol 42: 981–986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McErlean P, Shackelton LA, Lambert SB, Nissen MD, Sloots TP, Mackay IM. 2007. Characterisation of a newly identified human rhinovirus, HRV‐QPM, discovered in infants with bronchiolitis. J Clin Virol 39: 67–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller EK, Lu X, Erdman DD, Poehling KA, Zhu Y, Griffin MR, Hartert TV, Anderson LJ, Weinberg GA, Hall CB, Iwane MK, Edwards KM. 2007. Rhinovirus‐associated hospitalizations in young children. J Infect Dis 195: 773–781. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moes E, Vijgen L, Keyaerts E, Zlateva K, Li S, Maes P, Pyrc K, Berkhout B, van der Hoek L, Van Ranst M. 2005. A novel pancoronavirus RT‐PCR assay: Frequent detection of human coronavirus NL63 in children hospitalized with respiratory tract infections in Belgium. BMC Infect Dis 5: 6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray RS, Cai GY, Hoel K, Zhang JY, Soike KF, Cabirac GF. 1992. Coronavirus infects and causes demyelination in primate central nervous system. Virology 188: 274–284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pyrc K, Berkhout B, van der Hoek L. 2007. The novel human coronaviruses NL63 and HKU1. J Virol 81: 3051–3057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Resta S, Luby JP, Rosenfeld CR, Siegel JD. 1985. Isolation and propagation of a human enteric coronavirus. Science 229: 978–981. [DOI] [PubMed] [Google Scholar]
- Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, Icenogle JP, Penaranda S, Bankamp B, Maher K, Chen MH, Tong S, Tamin A, Lowe L, Frace M, DeRisi JL, Chen Q, Wang D, Erdman DD, Peret TC, Burns C, Ksiazek TG, Rollin PE, Sanchez A, Liffick S, Holloway B, Limor J, McCaustland K, Olsen‐Rasmussen M, Fouchier R, Gunther S, Osterhaus AD, Drosten C, Pallansch MA, Anderson LJ, Bellini WJ. 2003. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300: 1394–1399. [DOI] [PubMed] [Google Scholar]
- Saif LJ. 1996. Mucosal immunity: An overview and studies of enteric and respiratory coronavirus infections in a swine model of enteric disease. Vet Immunol Immunopathol 54: 163–169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simon A, Volz S, Hofling K, Kehl A, Tillman R, Muller A, Kupfer B, Eis‐Hubinger AM, Lentze MJ, Bode U, Schildgen O. 2007. Acute life threatening event (ALTE) in an infant with human coronavirus HCoV‐229E infection. Pediatr Pulmonol 42: 393–396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sloots TP, McErlean P, Speicher DJ, Arden KE, Nissen MD, Mackay IM. 2006. Evidence of human coronavirus HKU1 and human bocavirus in Australian children. J Clin Virol 35: 99–102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vabret A, Dina J, Gouarin S, Petitjean J, Corbet S, Freymuth F. 2006. Detection of the new human coronavirus HK U1: A report of 6 cases. Clin Infect Dis 42: 634–639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vabret A, Dina J, Gouarin S, Petitjean J, Tripey V, Brouard J, Freymuth F. 2008. Human (non‐severe acute respiratory syndrome) coronavirus infections in hospitalised children in France. J Paediatr Child Health 44: 176–181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vabret A, Mourez T, Dina J, van der Hoek L, Gouarin S, Petitjean J, Brouard J, Freymuth F. 2005. Human coronavirus NL63, France. Emerg Infect Dis 11: 1225–1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van der Hoek L, Pyrc K, Jebbink MF, Vermeulen‐Oost W, Berkhout RJ, Wolthers KC, Wertheim‐van Dillen PM, Kaandorp J, Spaargaren J, Berkhout B. 2004. Identification of a new human coronavirus. Nat Med 10: 368–373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van der Hoek L, Sure K, Ihorst G, Stang A, Pyrc K, Jebbink MF, Petersen G, Forster J, Berkhout B, Uberla K. 2005. Croup is associated with the novel coronavirus NL63. PLoS Med 2: e240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- WHO . 2003. The World Health Report 2003: Shaping the future. Geneva: World Health Organization. [Google Scholar]
- WHO . 2008. The Global Burden of Disease: 2004 Update. Geneva, Switzerland: WHO Press. [Google Scholar]
- Woo PC, Lau SK, Chu CM, Chan KH, Tsoi HW, Huang Y, Wong BH, Poon RW, Cai JJ, Luk WK, Poon LL, Wong SS, Guan Y, Peiris JS, Yuen KY. 2005. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol 79: 884–895. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.