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).

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]

See the list below:

• No distinction between confirmed, apparently isolated bocavirus-associated disease and any other nonspecific viral respiratory infection has been established.

• The most consistently reported symptoms include cough, fever, and rhinorrhea.

• A higher-than-expected rate of GI symptoms has been noted, with as many as 25% of patients experiencing some form of gastroenteritis. Other known pathogens were detected along with human bocavirus in 58% of stool samples in one study from Spain.[24] HBoV2 has been detected at a high frequency (17.2%) in stool samples of children with acute gastroenteritis, but also in a significant number (8.1%) of healthy controls.[6]

• Several reports of isolated human bocavirus in patients with wheezing episodes suggest that it primarily causes obstructive respiratory disease, is a secondary inflammatory response (similar to respiratory syncytial virus), or acts as a trigger to patients who are susceptible to reactive airways, such as those with preexisting asthma.

See the list below:

• The physical examination findings are similar to those of a typical viral respiratory infection.

• Patients with more severe lower respiratory tract disease may have wheezing, tachypnea, grunting (in younger children), and use of accessory muscles.

• Children with severe gastroenteritis may show signs of dehydration: poor skin turgor, sunken eyes, lethargy. A decrease in urine output (manifesting as fewer wet diapers in young infants) and a lack of tears when crying may be noticed.

See the list below:

• At this time, no testing tools for human bocavirus are readily available outside of the research setting.

• Because no evidence suggests that human bocavirus contributes to a particular clinical outcome that requires additional therapy (and because no specific therapy is available), testing for human bocavirus is not necessary.

• Research tools that have been used include the following:

  • DNA polymerase chain reaction (PCR) from nasopharyngeal aspirates and swabs

  • DNA PCR from peripheral blood

  • Electron microscopy of nasopharyngeal aspirates

• Preliminary studies have been performed to enable serologic detection of human bocavirus infection.

• Human bocavirus does not replicate in existing viral culture systems, but a report of successful culture in differentiated human respiratory epithelial cells has been made.[9] Peripheral WBC counts are generally normal (< 16,000/mL, with an average of approximately 10,000/mL). A raised C-reactive protein level has been occasionally noted but is not consistent.[11, 25, 26]

See the list below:

• Children who have had bocavirus detected during respiratory illness have been reported to have more focal chest radiography findings than are typically seen in most viral pneumonias (eg, bronchopneumonia or lobar consolidation) as opposed to findings typically seen in a diffuse interstitial pneumonia.

• Chest radiography findings are often abnormal; this may be a feature of sample bias because children who are more ill are the ones who have been tested for bocavirus in most studies (ie, those children ill enough to be hospitalized).

Acute respiratory illness due to bocavirus should be managed in a manner similar to most other viral respiratory infections.

• No antiviral medication is known to affect human bocavirus, and none has been proven to be of any clinical benefit.

• Symptomatic care is the mainstay of treatment.

• Supplemental oxygen may be required for serious infections that lead to pneumonia.

• Wheezing may be treated with bronchodilators. However, for wheezing episodes due to bronchiolitis in patients with respiratory syncytial virus infection, bronchodilators are of minimal benefit. The same may be true for human bocavirus; however, a therapeutic trial should probably be considered if the patient is in respiratory distress.

Acute gastroenteritis due to HBoV2 should be managed as with other viral gastrointestinal infections.

• Replacement of fluid losses, both acute and ongoing

• Management of any electrolyte disturbances, such as sodium or potassium

No medication is known to be effective in the treatment of human bocavirus infection. Treatment is largely supportive, as is the case with other viral respiratory infections.

No evidence suggests that human bocavirus contributes to a particular clinical outcome that requires additional therapy.