Association of Human Bocavirus 1 Infection with Respiratory Disease in Childhood Follow-up Study, Finland

Mira Meriluoto, Lea Hedman, Laura Tanner, Ville Simell, Marjaana Mäkinen, Satu Simell, Juha Mykkänen, Jan Korpelainen, Olli Ruuskanen, Jorma Ilonen, Mikael Knip, Olli Simell, Klaus Hedman, and Maria Söderlund-Venermo

Author affiliations: University of Helsinki, Helsinki, Finland (M. Meriluoto, L. Hedman, M. Knip, K. Hedman, M. Söderlund-Venermo); Haartman Institute, Helsinki (M. Meriluoto, L. Hedman, K. Hedman, M. Söderlund-Venermo); Helsinki University Central Hospital, Helsinki (L. Hedman, M. Knip, K. Hedman); University of Turku, Turku, Finland (L. Tanner, V. Simell, M. Mäkinen, S. Simell, J. Mykkänen, J. Korpelainen, O. Ruuskanen, J. Ilonen, O. Simell); University of Eastern Finland, Kuopio, Finland (J. Ilonen); Tampere University Hospital, Tampere, Finland (M. Knip); Folkhälsan Research Center, Helsinki (M. Knip)

Abstract

Human bocavirus 1 (HBoV1) DNA is frequently detected in the upper airways of young children with respiratory symptoms. Because of its persistence and frequent co-detection with other viruses, however, its etiologic role has remained controversial. During 2009–2011, using HBoV1 IgM, IgG, and IgG-avidity enzyme immunoassays and quantitative PCR, we examined 1,952 serum samples collected consecutively at 3- to 6-month intervals from 109 constitutionally healthy children from infancy to early adolescence. Primary HBoV1 infection, as indicated by seroconversion, appeared in 102 (94%) of 109 children at a mean age of 2.3 years; the remaining 7 children were IgG antibody positive from birth. Subsequent secondary infections or IgG antibody increases were evident in 38 children and IgG reversions in 10. Comparison of the seroconversion interval with the next sampling interval for clinical events indicated that HBoV1 primary infection, but not secondary immune response, was significantly associated with acute otitis media and respiratory illness.

Human bocavirus 1 (HBoV1), a new member of the Bocavirus genus of the family Parvoviridae, was discovered in 2005 by large-scale sequencing in nasopharyngeal samples from children (1). HBoV1 DNA has since been frequently detected by PCR in the upper airways of young children who have upper or lower respiratory tract illness (URTI, LRTI) and, less frequently, in their feces (2,3). Furthermore, 3 other bocaviruses, HBoV2, 3, and 4, were recently detected in human feces (4–6), and HBoV2 has been associated with acute gastroenteritis (5).

HBoV1 in the upper airways also occurs persistently or recurrently in asymptomatic children (7–11). Because of these characteristics and frequent co-detection with other viruses, the role of HBoV1 in respiratory illness has been questioned. Circumventing the PCR-related problems of prolonged or recurrent positivity and disclosing the association of HBoV1 infection with disease require a more reliable diagnosis that uses serum for PCR and antibody detection (12–16). By using serology, one can distinguish between primary and secondary HBoV1 infections. We recently detected secondary HBoV1 immunoactivations in immunocompetent adults (17), but no data exist on the clinical effects of such events or on their frequency in children. Furthermore, to our knowledge, no prospective studies with reliable diagnostics have been conducted to determine the clinical associations of primary HBoV1 infection.

We determined HBoV1 primary infection in relation to clinical symptoms among constitutionally healthy children who were serologically followed from infancy up to age 13 years. In addition, we investigated the kinetics of HBoV1 viremia and IgG and IgM antibody responses, IgG avidity maturation, and the occurrence and clinical effects of secondary infections or immunoactivations.