Pediatric Bocavirus

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).

The genome of human bocavirus. The 4 genes are labeled based on their presumed function, according to homologous genes in other parvoviruses. Nonstructural protein 1 (NS1) is a DNA-binding protein involved in gene transcription. NP1 is also nonstructural and is a highly conserved protein of unknown function. The capsid proteins are viral protein 1 (VP1) and viral protein 2 (VP2).

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An electron micrograph of canine parvovirus, which is closely related to human bocavirus.

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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] ).

Frequency

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.

Mortality/Morbidity

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]

Race

No racial predilection is known.

Sex

No gender predilection is known.

Age

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]