Pediatric Bocavirus

Pediatric Bocavirus

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Human bocavirus (a member of the Parvoviridae virus family) is a newly described human pathogen that has been associated with lower respiratory tract and gastrointestinal infections, predominantly in children.^[1]It is a very small (approximately 20 nm), nonenveloped virus with a single-stranded negative-sense DNA genome (see following images).

It is one of only 2 known human parvovirus pathogens; the other is parvovirus B19, which causes erythema infectiosum (fifth disease or slapped-cheek disease), papular purpuric glove and stocking syndrome (PPGSS), and more serious illnesses such as hydrops fetalis and aplastic crises in people with sickle cell disease. In general, parvoviruses are more important as veterinary pathogens. The Dependovirus adeno-associated virus (AAV) is a small parvovirus that requires a helper co-infection to replicate (either adenovirus or herpes simplex virus) and is not directly associated with a disease in its own right.

There are 4 genetically distinct, but related human bocaviruses. Using advanced molecular techniques, human bocavirus (HBoV) was first isolated in 2005 in upper respiratory secretions of acutely ill children in Sweden.^[2]Analysis of samples from children hospitalized with lower respiratory tract infections and children with acute wheezing episodes has provided infection rates of 2-20% from various areas of the world. The high rate of infection, along with the codetection of other viral pathogens (or simply not ruling out other common virus infections in some studies), has caused some researchers to question whether human bocavirus is a primary cause of disease, a contributor to more severe disease, or simply a passenger virus that is coincidentally found with other infections.^[3]

Human bocaviruses 2 and 3 (HBoV2 and HBoV3) were reported in stool specimens from children in 2009 from the United States and Australia.^{[4, 5, 6]}HBoV2 has been implicated in some cases of acute gastroenteritis^[7], whereas HBoV3, although detected in stool at low frequencies, has an uncertain role in disease. HBoV4 has also been reported from stool. HBoV1 appears to be a primarily respiratory infection.^[8]

Bocavirus was putatively linked to the bovine parvovirus and canine minutevirus by genetic and amino acid sequence similarities. “Bovine” and “canine” lead to the “boca” in bocavirus. One recent report of a culture system using differentiated human epithelial cells has permitted more detailed research of its replication.^[9]A real-time multiplex PCR has been developed.^[10]

The pathophysiology remains largely unknown due to uncertainty about whether bocavirus is even a pathogen in its own right.

Human bocavirus is known to replicate to high titers in the human respiratory tract and probably replicates in replicating epithelial cells; however, whether it grows elsewhere is unknown.^[11]In animals, it can be found in respiratory and gut epithelium and lymphoid tissue.

Human bocavirus DNA can be detected in peripheral blood of children with respiratory symptoms and asymptomatic controls; however, a definite trend towards higher levels of DNAemia is observed in symptomatic children, and DNA levels decline with resolution of symptoms, suggesting that systemic infection is a feature of more acute infection.^{[11, 12]}

High-titers are arguably a reflection of enhanced replication of a cell-associated pathogen when inflammation due to another virus is present. Human bocavirus is frequently found in the presence of another virus (up to 90% codetection in some studies). Often, the viral load of the co-infection is relatively low, which supports the idea that the symptoms may have been worsened by the presence of the infection because these samples are usually taken from hospitalized patients, who are, by definition, suffering from more serious respiratory disease. The high rate of co-infection may be due to the fact that HBoV has been shown to have prolonged shedding even from asymptomatic children; thus, detection of HBoV may reflect an infection several weeks or months prior to a respiratory event caused by another virus.^{[13, 14, 15]}

Higher titers of HBoV in respiratory secretions have been associated with increased wheezing, suggesting a causal role.^[16]Severe disease has been reported when other known respiratory infections have been ruled out.^{[17, 18]}Four children with encephalitis were reported from Japan with HBoV 1 or HBoV2 detected in their spinal fluid and/or serum.^[19]

In the absence of good animal models, concluding which paradigm is correct is impossible. In fact, what may be true for one virus co-infection may not be true for another. Others have also recommended caution in interpreting molecular findings of HBoV associated with human disease.^[20]

HBoV2 may have a role in acute gastroenteritis, being detected frequently in stool specimens (the third most common after rotavirus and astrovirus in one study^[6]).

United States

The limited data collected in the United States have placed the prevalence of detectable human bocavirus in tested specimens at around 5%. However, worldwide data put the rate from 1.5-19%, depending on the population studied.

Many caveats are noted when interpreting these numbers, not least of which is that data may be skewed by preferential sampling during the winter months (when respiratory viruses are typically more prevalent). Because of this, determining whether human bocavirus has the typical seasonality of known respiratory infections or whether it is more like the enteroviruses and has a higher incidence during the summer months is impossible.

No reliable data are available on HBoV2, HBoV3 of HBoV4.

International

Human bocavirus has a worldwide distribution and has been detected in Europe, Africa, Asia, North America, Australia, and the Middle East. The reported infection rates widely vary (2-20%); however, determining whether these rates are truly comparable is impossible because the studies have varied in the populations tested and the methodologies used.

No firm evidence exists that human bocavirus contributes to a particular clinical outcome that requires additional therapy. HBoV has been implicated in childhood respiratory disease requiring hospitalization, and HBoV2 has been implicated in acute gastroenteritis. HBoV3 has an uncertain role in human disease but was detected initially in stool samples.

A case report of apparently disseminated HBoV2 resulting in death was published in 2013.^[21]A few reports, apparently well documented and supported by molecular diagnostics, of encephalitis from HBoV have been made.^[22]

No racial predilection is known.

No gender predilection is known.

Human bocavirus has largely been isolated from children with respiratory illnesses, mostly children younger than 2 years. The adult virus prevalence has not yet been sufficiently investigated to determine accurate rates of infection or carriage but appears to be low. One study from Japan suggests that immunity is acquired and protective, with lower viral prevalence associated with higher specific antibody levels in older patients (the study included patients aged 0 mo to 41 y).^[23]

Guido M, Tumolo MR, Verri T, Romano A, Serio F, De Giorgi M, et al. Human bocavirus: Current knowledge and future challenges. World J Gastroenterol. 2016 Oct 21. 22 (39):8684-8697. [Medline]. [Full Text].

Allander T, Tammi MT, Eriksson M, et al. Cloning of a human parvovirus by molecular screening of respiratory tract samples. Proc Natl Acad Sci U S A. 2005 Sep 6. 102(36):12891-6. [Medline].

Schildgen O, Müller A, Allander T, Mackay IM, Völz S, Kupfer B, et al. Human bocavirus: passenger or pathogen in acute respiratory tract infections?. Clin Microbiol Rev. 2008 Apr. 21(2):291-304, table of contents. [Medline]. [Full Text].

Kapoor A, Slikas E, Simmonds P, Chieochansin T, Naeem A, Shaukat S, et al. A newly identified bocavirus species in human stool. J Infect Dis. 2009 Jan 15. 199(2):196-200. [Medline]. [Full Text].

Chow BD, Ou Z, Esper FP. Newly recognized bocaviruses (HBoV, HBoV2) in children and adults with gastrointestinal illness in the United States. J Clin Virol. 2010 Feb. 47(2):143-7. [Medline].

Arthur JL, Higgins GD, Davidson GP, Givney RC, Ratcliff RM. A novel bocavirus associated with acute gastroenteritis in Australian children. PLoS Pathog. 2009 Apr. 5(4):e1000391. [Medline]. [Full Text].

De R, Liu L, Qian Y, Zhu R, Deng J, Wang F, et al. Risk of acute gastroenteritis associated with human bocavirus infection in children: A systematic review and meta-analysis. PLoS One. 2017. 12 (9):e0184833. [Medline]. [Full Text].

Zhao M, Zhu R, Qian Y, Deng J, Wang F, Sun Y, et al. Prevalence and Phylogenetic Analysis of Human Bocaviruses 1-4 in Pediatric Patients with Various Infectious Diseases. PLoS One. 2016. 11 (8):e0160603. [Medline]. [Full Text].

Dijkman R, Koekkoek SM, Molenkamp R, Schildgen O, van der Hoek L. Human bocavirus can be cultured in differentiated human airway epithelial cells. J Virol. 2009 Aug. 83(15):7739-48. [Medline]. [Full Text].

Lassauniére R, Kresfelder T, Venter M. A novel multiplex real-time RT-PCR assay with FRET hybridization probes for the detection and quantitation of 13 respiratory viruses. J Virol Methods. 2010 Feb 11. [Medline].

Allander T, Jartti T, Gupta S, et al. Human bocavirus and acute wheezing in children. Clin Infect Dis. 2007 Apr 1. 44(7):904-10. [Medline].

Fry AM, Lu X, Chittaganpitch M, Peret T, et al. Human bocavirus: a novel parvovirus epidemiologically associated with pneumonia requiring hospitalization in Thailand. J Infect Dis. 2007 Apr 1. 195(7):1038-45. [Medline].

Martin ET, Fairchok MP, Kuypers J, et al. Frequent and prolonged shedding of bocavirus in young children attending daycare. J Infect Dis. 2010 Jun 1. 201(11):1625-32. [Medline]. [Full Text].

Lehtoranta L, Soderlund-Venermo M, Nokso-Koivisto J, et al. Human bocavirus in the nasopharynx of otitis-prone children. Int J Pediatr Otorhinolaryngol. 2012 Feb. 76(2):206-11. [Medline].

Blessing K, Neske F, Herre U, Kreth HW, Weissbrich B. Prolonged detection of human bocavirus DNA in nasopharyngeal aspirates of children with respiratory tract disease. Pediatr Infect Dis J. 2009 Nov. 28(11):1018-9. [Medline].

Deng Y, Gu X, Zhao X, et al. High viral load of human bocavirus correlates with duration of wheezing in children with severe lower respiratory tract infection. PLoS One. 2012. 7(3):e34353. [Medline]. [Full Text].

Korner RW, Soderlund-Venermo M, van Koningsbruggen-Rietschel S, Kaiser R, Malecki M, Schildgen O. Severe human bocavirus infection, Germany. Emerg Infect Dis. 2011 Dec. 17(12):2303-5. [Medline]. [Full Text].

Edner N, Castillo-Rodas P, Falk L, Hedman K, Söderlund-Venermo M, Allander T. Life-threatening respiratory tract disease with human bocavirus-1 infection in a 4-year-old child. J Clin Microbiol. 2012 Feb. 50(2):531-2. [Medline]. [Full Text].

Mitui MT, Tabib SM, Matsumoto T, et al. Detection of human bocavirus in the cerebrospinal fluid of children with encephalitis. Clin Infect Dis. 2012 Apr. 54(7):964-7. [Medline].

Korppi M. Polymerase chain reaction in respiratory samples alone is not a reliable marker of bocavirus infection. Pediatr Pulmonol. 2013 Oct 24. [Medline].

Brebion A, Vanlieferinghen P, Déchelotte P, Boutry M, Peigue-Lafeuille H, Henquell C. Fatal sub-acute myocarditis associated with human bocavirus 2 in a 13-month-old child. J Clin Microbiol. 2013 Dec 26. [Medline].

Mori D, Ranawaka U, Yamada K, Rajindrajith S, Miya K, Perera HK, et al. Human bocavirus in patients with encephalitis, Sri Lanka, 2009-2010. Emerg Infect Dis. 2013 Nov. 19(11):1859-62. [Medline]. [Full Text].

Endo R, Ishiguro N, Kikuta H, Teramoto S, Shirkoohi R, Ma X, et al. Seroepidemiology of human bocavirus in Hokkaido prefecture, Japan. J Clin Microbiol. 2007 Oct. 45(10):3218-23. [Medline].

Vicente D, Cilla G, Montes M, et al. Human bocavirus, a respiratory and enteric virus. Emerg Infect Dis. 2007 Apr. 13(4):636-7. [Medline].

Ma X, Endo R, Ishiguro N, et al. Detection of human bocavirus in Japanese children with lower respiratory tract infections. J Clin Microbiol. 2006 Mar. 44(3):1132-4. [Medline].

Volz S, Schildgen O, Klinkenberg D, et al. Prospective study of Human Bocavirus (HBoV) infection in a pediatric university hospital in Germany 2005/2006. J Clin Virol. 2007 Nov. 40(3):229-35. [Medline].

Kapoor A, Simmonds P, Slikas E, et al. Human bocaviruses are highly diverse, dispersed, recombination prone, and prevalent in enteric infections. J Infect Dis. 2010 Jun 1. 201(11):1633-43. [Medline].

Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP Assistant Professor of Pediatrics, Co-Director of Antimicrobial Stewardship, Medical Director, Division of Pediatric Infectious Diseases and Immunology, Connecticut Children’s Medical Center

Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics

Disclosure: Received research grant from: Cubist<br/>Received income in an amount equal to or greater than $250 from: Horizon Pharmaceuticals, Shire<br/>Medico legal consulting for: Various.

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa

Disclosure: Received research grant from: Pfizer;GlaxoSmithKline;AstraZeneca;Merck;American Academy of Pediatrics, Novavax, Regeneron, Diassess, Actelion<br/>Received income in an amount equal to or greater than $250 from: Sanofi Pasteur.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Russell W Steele, MD Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, Southern Medical Association

Disclosure: Nothing to disclose.

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