The Role of Human Coronaviruses in Children Hospitalized for Acute Bronchiolitis, Acute Gastroenteritis, and Febrile Seizures: A 2-Year Prospective Study

Monika Jevšnik, Andrej Steyer, Marko Pokorn, Tatjana Mrvič, Štefan Grosek, Franc Strle, Lara Lusa, Miroslav Petrovec, Monika Jevšnik, Andrej Steyer, Marko Pokorn, Tatjana Mrvič, Štefan Grosek, Franc Strle, Lara Lusa, Miroslav Petrovec

Abstract

Human coronaviruses (HCoVs) are associated with a variety of clinical presentations in children, but their role in disease remains uncertain. The objective of our prospective study was to investigate HCoVs associations with various clinical presentations in hospitalized children up to 6 years of age. Children hospitalized with acute bronchiolitis (AB), acute gastroenteritis (AGE), or febrile seizures (FS), and children admitted for elective surgical procedures (healthy controls) were included in the study. In patients with AB, AGE, and FS, a nasopharyngeal (NP) swab and blood sample were obtained upon admission and the follow-up visit 14 days later, whereas in children with AGE a stool sample was also acquired upon admission; in healthy controls a NP swab and stool sample were taken upon admission. Amplification of polymerase 1b gene was used to detect HCoVs in the specimens. HCoVs-positive specimens were also examined for the presence of several other viruses. HCoVs were most often detected in children with FS (19/192, 9.9%, 95% CI: 6-15%), followed by children with AGE (19/218, 8.7%, 95% CI: 5.3-13.3%) and AB (20/308, 6.5%, 95% CI: 4.0-9.8%). The presence of other viruses was a common finding, most frequent in the group of children with AB (19/20, 95%, 95% CI: 75.1-99.8%), followed by FS (10/19, 52.6%, 95% CI: 28.9-75.6%) and AGE (7/19, 36.8%, 95% CI: 16.3-61.6%). In healthy control children HCoVs were detected in 3/156 (1.9%, 95% CI: 0.4-5.5%) NP swabs and 1/150 (0.7%, 95% CI: 0.02-3.3%) stool samples. It seems that an etiological role of HCoVs is most likely in children with FS, considering that they had a higher proportion of positive HCoVs results than patients with AB and those with AGE, and had the highest viral load; however, the co-detection of other viruses was 52.6%.

Trial registration: ClinicalTrials.gov NCT00987519.

Conflict of interest statement

Competing Interests: The authors of this manuscript have read the journal's policy and have the following competing interests: Marko Pokorn received lecture fees from GSK, Pfizer and MSD. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Seasonal distribution of HCoVs-positive samples.
Fig 1. Seasonal distribution of HCoVs-positive samples.
Human coronaviruses (HCoVs), acute bronchiolitis (AB), febrile seizures (FS), and acute gastroenteritis (AGE).
Fig 2. The Ct value measured for…
Fig 2. The Ct value measured for HCoV-positive patients at baseline and follow-up examination in nasopharyngeal swabs.
HCoV species were not determined due to low viral load (Untyped); HCoV species (229E, HKU1, NL63, OC43).

References

    1. Pene F, Merlat A, Vabret A, Rozenberg F, Buzyn A, Dreyfus F, et al. Coronavirus 229E-related pneumonia in immunocompromised patients. Clin Infect Dis. 2003;37(7):929–32. .
    1. Vabret A, Mourez T, Gouarin S, Petitjean J, Freymuth F. An outbreak of coronavirus OC43 respiratory infection in Normandy, France. Clin Infect Dis. 2003;36(8):985–9. .
    1. Woo PC, Lau SK, Tsoi HW, Huang Y, Poon RW, Chu CM, et al. Clinical and molecular epidemiological features of coronavirus HKU1-associated community-acquired pneumonia. The Journal of infectious diseases. 2005;192(11):1898–907. .
    1. Kuypers J, Martin ET, Heugel J, Wright N, Morrow R, Englund JA. Clinical disease in children associated with newly described coronavirus subtypes. Pediatrics. 2007;119(1):e70–6. .
    1. Talbot HK, Crowe JE Jr, Edwards KM, Griffin MR, Zhu Y, Weinberg GA, et al. Coronavirus infection and hospitalizations for acute respiratory illness in young children. Journal of medical virology. 2009;81(5):853–6. 10.1002/jmv.21443
    1. van der Hoek L, Sure K, Ihorst G, Stang A, Pyrc K, Jebbink MF, et al. Croup is associated with the novel coronavirus NL63. PLoS medicine. 2005;2(8):e240 .
    1. Wu PS, Chang LY, Berkhout B, van der Hoek L, Lu CY, Kao CL, et al. Clinical manifestations of human coronavirus NL63 infection in children in Taiwan. European journal of pediatrics. 2008;167(1):75–80. .
    1. Han TH, Chung JY, Kim SW, Hwang ES. Human Coronavirus-NL63 infections in Korean children, 2004–2006. Journal of Clinical Virology. 2007;38(1):27–31. .
    1. Suzuki A, Okamoto M, Ohmi A, Watanabe O, Miyabayashi S, Nishimura H. Detection of human coronavirus-NL63 in children in Japan. The Pediatric infectious disease journal. 2005;24(7):645–6. .
    1. Ebihara T, Endo R, Ma X, Ishiguro N, Kikuta H. Detection of human coronavirus NL63 in young children with bronchiolitis. Journal of medical virology. 2005;75(3):463–5. .
    1. Vabret A, Mourez T, Dina J, van der Hoek L, Gouarin S, Petitjean J, et al. Human coronavirus NL63, France. Emerging infectious diseases. 2005;11(8):1225–9. .
    1. Lau SK, Woo PC, Yip CC, Tse H, Tsoi HW, Cheng VC, et al. Coronavirus HKU1 and other coronavirus infections in Hong Kong. Journa of Clinical Microbiology. 2006;44(6):2063–71. .
    1. Kuypers J, Martin ET, Heugel J, Wright N, Morrow R, Englund JA. Clinical disease in children associated with newly described coronavirus subtypes. Pediatrics. 2007;119(1):e70–6. .
    1. Bosis S, Esposito S, Niesters HG, Tremolati E, Pas S, Principi N, et al. Coronavirus HKU1 in an Italian pre-term infant with bronchiolitis. Journal of Clinical Virology. 2007;38(3):251–3. .
    1. Risku M, Lappalainen S, Rasanen S, Vesikari T. Detection of human coronaviruses in children with acute gastroenteritis. Journal of Clinical Virology. 2010;48(1):27–30. 10.1016/j.jcv.2010.02.013
    1. Esper F, Ou Z, Huang YT. Human coronaviruses are uncommon in patients with gastrointestinal illness. Journal of Clinical Virology. 2010;48(2):131–3. 10.1016/j.jcv.2010.03.007
    1. Clarke SK, Caul EO, Egglestone SI. The human enteric coronaviruses. Postgraduate medical journal. 1979;55(640):135–42. .
    1. Stewart JN, Mounir S, Talbot PJ. Human coronavirus gene expression in the brains of multiple sclerosis patients. Virology. 1992;191(1):502–5. .
    1. Yeh EA, Collins A, Cohen ME, Duffner PK, Faden H. Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis. Pediatrics. 2004;113(1 Pt 1):e73–6. .
    1. Jevsnik M, Steyer A, Zrim T, Pokorn M, Mrvic T, Grosek S, et al. Detection of human coronaviruses in simultaneously collected stool samples and nasopharyngeal swabs from hospitalized children with acute gastroenteritis. Virology journal. 2013;10:46 Epub 2013/02/06. 10.1186/1743-422X-10-46
    1. Diallo IS, Hewitson G, Wright L, Rodwell BJ, Corney BG. Detection of equine herpesvirus type 1 using a real-time polymerase chain reaction. Journal of virological methods. 2006;131(1):92–8. Epub 2005/09/03. 10.1016/j.jviromet.2005.07.010 .
    1. Mankoc S, Hostnik P, Grom J, Toplak I, Klobucar I, Kosec M, et al. Comparison of different molecular methods for assessment of equine arteritis virus (EAV) infection: a novel one-step MGB real-time RT-PCR assay, PCR-ELISA and classical RT-PCR for detection of highly diverse sequences of Slovenian EAV variants. Journal of virological methods. 2007;146(1–2):341–54. .
    1. Kuypers J, Wright N, Morrow R. Evaluation of quantitative and type-specific real-time RT-PCR assays for detection of respiratory syncytial virus in respiratory specimens from children. Journal of clinical virology. 2004;31(2):123–9. Epub 2004/09/15. 10.1016/j.jcv.2004.03.018 .
    1. Kuypers J, Wright N, Ferrenberg J, Huang ML, Cent A, Corey L, et al. Comparison of real-time PCR assays with fluorescent-antibody assays for diagnosis of respiratory virus infections in children. Journal of clinical microbiology. 2006;44(7):2382–8. Epub 2006/07/11. 10.1128/JCM.00216-06
    1. Daum LT, Canas LC, Arulanandam BP, Niemeyer D, Valdes JJ, Chambers JP. Real-time RT-PCR assays for type and subtype detection of influenza A and B viruses. Influenza and other respiratory viruses. 2007;1(4):167–75. Epub 2007/07/01. 10.1111/j.1750-2659.2007.00024.x .
    1. Maertzdorf J, Wang CK, Brown JB, Quinto JD, Chu M, de Graaf M, et al. Real-time reverse transcriptase PCR assay for detection of human metapneumoviruses from all known genetic lineages. Journal of clinical microbiology. 2004;42(3):981–6. Epub 2004/03/09.
    1. Lu X, Chittaganpitch M, Olsen SJ, Mackay IM, Sloots TP, Fry AM, et al. Real-time PCR assays for detection of bocavirus in human specimens. Journal of clinical microbiology. 2006;44(9):3231–5. .
    1. De Vos N, Vankeerberghen A, Vaeyens F, Van Vaerenbergh K, Boel A, De Beenhouwer H. Simultaneous detection of human bocavirus and adenovirus by multiplex real-time PCR in a Belgian paediatric population. European journal of clinical microbiology & infectious diseases. 2009;28(11):1305–10. Epub 2009/08/26. 10.1007/s10096-009-0780-y .
    1. Scheltinga SA, Templeton KE, Beersma MF, Claas EC. Diagnosis of human metapneumovirus and rhinovirus in patients with respiratory tract infections by an internally controlled multiplex real-time RNA PCR. Journal of clinical virology. 2005;33(4):306–11. Epub 2005/07/05. 10.1016/j.jcv.2004.08.021 .
    1. Kageyama T, Kojima S, Shinohara M, Uchida K, Fukushi S, Hoshino FB, et al. Broadly reactive and highly sensitive assay for Norwalk-like viruses based on real-time quantitative reverse transcription-PCR. Journal of clinical microbiology. 2003;41(4):1548–57. .
    1. Svraka S, van der Veer B, Duizer E, Dekkers J, Koopmans M, Vennema H. Novel approach for detection of enteric viruses to enable syndrome surveillance of acute viral gastroenteritis. Journal of clinical microbiology. 2009;47(6):1674–9. Epub 2009/04/03. 10.1128/JCM.00307-09
    1. R CoreTeam. R: A language and environment for statistical computing. R Foundation for statistical Computing Vienna, Austria: 2015. Available from: .
    1. Vabret A, Dina J, Gouarin S, Petitjean J, Corbet S, Freymuth F. Detection of the new human coronavirus HKU1: a report of 6 cases. Clinical Infectious Diseases. 2006;42(5):634–9. .
    1. Woo PC, Yuen KY, Lau SK. Epidemiology of coronavirus-associated respiratory tract infections and the role of rapid diagnostic tests: a prospective study. Hong Kong medical journal = Xianggang yi xue za zhi / Hong Kong Academy of Medicine. 2012;18 Suppl 2:22–4. Epub 2012/02/15. .
    1. Esposito S, Bosis S, Niesters HG, Tremolati E, Begliatti E, Rognoni A, et al. Impact of human coronavirus infections in otherwise healthy children who attended an emergency department. Journal of medical virology. 2006;78(12):1609–15. .
    1. Gaunt ER, Hardie A, Claas EC, Simmonds P, Templeton KE. 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. Journal of clinical microbiology. 2010;48(8):2940–7. 10.1128/JCM.00636-10
    1. Kistler A, Avila PC, Rouskin S, Wang D, Ward T, Yagi S, et al. Pan-viral screening of respiratory tract infections in adults with and without asthma reveals unexpected human coronavirus and human rhinovirus diversity. The Journal of infectious diseases. 2007;196(6):817–25. .
    1. Kristoffersen AW, Nordbo SA, Rognlien AG, Christensen A, Dollner H. Coronavirus causes lower respiratory tract infections less frequently than RSV in hospitalized Norwegian children. The Pediatric infectious disease journal. 2011;30(4):279–83. 10.1097/INF.0b013e3181fcb159
    1. Miller EK, Gebretsadik T, Carroll KN, Dupont WD, Mohamed YA, Morin LL, et al. Viral etiologies of infant bronchiolitis, croup and upper respiratory illness during 4 consecutive years. The Pediatric infectious disease journal. 2013;32(9):950–5. 10.1097/INF.0b013e31829b7e43
    1. Paloniemi M, Lappalainen S, Vesikari T. Commonly circulating human coronaviruses do not have a significant role in the etiology of gastrointestinal infections in hospitalized children. J Clin Virol. 2015;62:114–7. 10.1016/j.jcv.2014.10.017 .
    1. Brian DA, Baric RS. Coronavirus genome structure and replication. Current topics in microbiology and immunology. 2005;287:1–30. .
    1. Desforges M, Le Coupanec A, Stodola JK, Meessen-Pinard M, Talbot PJ. Human coronaviruses: viral and cellular factors involved in neuroinvasiveness and neuropathogenesis. Virus research. 2014;194:145–58. 10.1016/j.virusres.2014.09.011 .
    1. Chiu SS, Chan KH, Chu KW, Kwan SW, Guan Y, Poon LL, et al. Human coronavirus NL63 infection and other coronavirus infections in children hospitalized with acute respiratory disease in Hong Kong, China. Clinical infectious diseases. 2005;40(12):1721–9. .
    1. Leung TF, Li CY, Lam WY, Wong GW, Cheuk E, Ip M, et al. Epidemiology and clinical presentations of human coronavirus NL63 infections in hong kong children. Journal of clinical microbiology. 2009;47(11):3486–92. 10.1128/JCM.00832-09
    1. Jevsnik M, Ursic T, Zigon N, Lusa L, Krivec U, Petrovec M. Coronavirus infections in hospitalized pediatric patients with acute respiratory tract disease. BMC Infect Dis. 2012;12:365 10.1186/1471-2334-12-365
    1. Woo PC, Yuen KY, Lau SK. Epidemiology of coronavirus-associated respiratory tract infections and the role of rapid diagnostic tests: a prospective study. Hong Kong Medical Journal. 2012;18 Suppl 2:22–4. .
    1. Matoba Y, Abiko C, Ikeda T, Aoki Y, Suzuki Y, Yahagi K, et al. Detection of the human coronavirus 229E, HKU1, NL63, and OC43 between 2010 and 2013 in Yamagata, Japan. Japanese journal of infectious diseases. 2015;68(2):138–41. 10.7883/yoken.JJID.2014.266 .
    1. Jin Y, Zhang RF, Xie ZP, Yan KL, Gao HC, Song JR, et al. Newly identified respiratory viruses associated with acute lower respiratory tract infections in children in Lanzou, China, from 2006 to 2009. Clin Microbiol Infect. 2012;18(1):74–80. 10.1111/j.1469-0691.2011.03541.x .
    1. Stempel HE, Martin ET, Kuypers J, Englund JA, Zerr DM. Multiple viral respiratory pathogens in children with bronchiolitis. Acta paediatrica. 2009;98(1):123–6. Epub 2008/09/13. 10.1111/j.1651-2227.2008.01023.x
    1. Chen YW, Huang YC, Ho TH, Huang CG, Tsao KC, Lin TY. Viral etiology of bronchiolitis among pediatric inpatients in northern Taiwan with emphasis on newly identified respiratory viruses. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2014;47(2):116–21. 10.1016/j.jmii.2012.08.012 .

Source: PubMed

3
Sottoscrivi