Bocavirus: What is it? Pathogenesis, Causes, Symptoms, Diagnosis, Treatment and Long-Term Consequences

HBV has been found in individuals of all ages, although it mainly affects babies 6-24 months with respiratory symptoms.

Human bocavirus ( HBV ) is a parvovirus isolated about a decade ago and is found worldwide in respiratory samples, primarily in early life and in children 6 to 24 months of age with acute respiratory infection , and in samples of feces, from patients with gastroenteritis .

Human bocavirus (HBV) is a parvovirus that was first identified in 2005 using a protocol based on DNase treatment, random PCR amplification, high-throughput sequencing, and bioinformatic analysis.

When this virus detection technique was initially applied to nasopharyngeal swabs and washes from children with unresolved respiratory tract infections, it gave a positive result rate of 3.1%; therefore, HBV was proposed to be a pathogen that causes respiratory tract diseases.

Subsequently, three additional subtypes of HBV were identified in human stool samples, termed HBV 2, HBV 3, and HBV 4 to differentiate them from the first isolated subtype, termed HBV 1.

In particular, studies of both respiratory and fecal samples have demonstrated the presence of HBV in association with other potential pathogens, leading to the hypothesis that the virus may be a harmless passenger rather than a true pathogen.

Additionally, the virus has been detected in other biological samples, including blood, saliva, feces, and urine, as well as environmental samples, including river water and sewage. Conversely, recent research has raised concerns about its presence in transfusion medicine.

However, according to Koch’s modified postulates, the virus cannot yet be confirmed as a causative agent of the disease due to the lack of animal models and / or due to the difficulties to replicate it in cells cultured in vitro.

Therefore, research and discussion on the potential role of this pathogen (alone or in combination with other types of viruses) in patients with respiratory infections and gastroenteritis is ongoing.

Pathogenesis

The pathogenesis of HBV remains poorly characterized, mainly due to the lack of specific cell lines for the cultivation of viruses or experimental animal models.

The first study to present an in vitro culture system for HBV dates back to 2009, in which pseudostratified HAE-ALI, derived from primary human bronchial epithelial cells, was used as a tool for HBV replication. .

The HAE-ALI model was previously used to infect a wide range of respiratory RNA viruses, such as influenza viruses and human coronaviruses, among others, from the apical surface, as opposed to respiratory DNA viruses, which were achieved only from the basolateral surface.

HBoV1 virions are capable of productively and persistently infecting HAE on the apical and basolateral surfaces.

However, a consequence of this infection may be the induction of airway epithelial damage, evidenced by loss of cilia, rupture of the tight junctional barrier, and hypertrophy of epithelial cells.

The virus enters the host through the respiratory tract and through the bloodstream or by direct ingestion, reaching the gastrointestinal tract.

HBV 1 has been detected in the respiratory and gastrointestinal tracts. Several studies have shown the association between HBoV1 and the upper and lower respiratory tract.

In this sense, the most frequently described clinical presentation of HBV 1 infection includes:

HBV 1 DNA has also been found in stool samples from adult patients with gastrointestinal manifestations of nausea, vomiting, and diarrhea .

However, the HBV 1 load in stool samples from pediatric patients with acute gastroenteritis was reported to be lower than the viral load in respiratory tract samples.

In fact, a median viral load of 1.88 × 104 genome / ml has been reported for stool samples, which is lower than that found in nasopharyngeal aspirates (NPCs) from patients with respiratory infections (4.9 × 10 3 copies / ml .

HBV 2, as well as the other genotypes, are more frequently found in stool samples, and HBV 2, and possibly HBV 3, is associated with gastroenteritis. Among these, HBV 2 has been the only species isolated from APN from children hospitalized with acute respiratory infections.

More recent data show that HBV can be directly and specifically detected in tissues such as the duodenum, paranasal sinus mucosa, and intestinal biopsies.

Epidemiology (causes) of bocavirus infection

HBV has a worldwide distribution; Its transmission and infection occur throughout the year, but it is predominant during the winter and spring months.

The worldwide distribution of HBV involves infections of the respiratory tract and gastrointestinal tract (as evidenced by stool samples) of children and adults in Europe, Asia, the Americas, Africa, and Australia.

The global prevalence of infection was estimated based on a search for articles published in the Medline database from September 6, 2005 (the year of HBV discovery) to March 15, 2016, and which includes studies evaluating the respiratory and gastrointestinal infection.

For each country, estimates of prevalence, 95% confidence intervals (CI), and percentage of co-infections were calculated based on pooled data from all eligible studies and data was extracted into a customized database.

In total, 357 reports were used on the prevalence of HBV correlated with respiratory diseases and gastrointestinal infections.

HBV seroprevalence is age-related and ranges from about 40% in children between 18 and 23 months of age, to nearly 100% in children older than 2 years, with an average of 76.6% in children and 96% in children. Adults.

In contrast, the observed discrepancy in HBoV2 seroprevalence (70.5% vs. 20.4%) is more likely due to differences in the methods used.

In fact, although the enzyme-linked immunosorbent assay (ELISA) indicates the exposure rate of accumulated infections, the PCR results only reveal an ongoing infection.

Symptoms of bocavirus infection

Common symptoms:

  • Cough : the most common. 25% of cases develop whooping cough as a spasmodic cough.
  • Nasal congestion.
  • Fever.
  • Difficulty breathing.
  • Sickness.
  • Diarrhea.

Less frequent symptoms:

  • Conjunctivitis .
  • Eruption.
  • Maculopapular erythema (small, red, raised flat rashes).

Most of the time it is seen on the chest, but few rashes can also be seen on the face.

Diagnosis

For many years, the diagnostic tools available for the identification of the etiologic agents associated with respiratory and gastroenteric diseases have been limited.

Initially, the main method for detecting HBV infections in respiratory and gastrointestinal samples was represented by a direct tool, namely conventional PCR, which was followed by nested and real-time (RT) –PCR.

PCR techniques allow the isolation of viral genome fragments from NPA, bronchoalveolar, stool, serum and urine samples by amplifying NP1, NS1 and / or the VP1 / 2 gene regions, or by other detection based on nucleic acid.

Treatment of bocavirus infection

Probiotics help shorten clinical episodes.

So far there is no specific antiviral therapy recommended against the human mouth virus. However, the studies carried out show a definite beneficial effect of the administration of probiotics.

Probiotics shorten the duration of episodes and decrease the severity of symptoms by approximately 25-60%.

Therefore, at present, a daily dose of 10 to 10 Lactobacillus Acidophillus colony units (NCFM) from November to April (inclusive) each year is recommended. This can also be administered in combination with Bifidobacterium Lactis (B1-07).

Both lactobacilli and bifidobateriun are considered safe for long-term use. However, they should only be administered to healthy children, under the supervision of the attending physician.

The incidence of HBV1 infection in children younger than 6 months is found to be significantly low. Most babies under 6 months. are breastfed. Human breast milk is known to have prebiotic and probiotic properties.

Therefore, this 6-month probiotic regimen may even be of prophylactic value in otherwise healthy children.

Long-term consequences

There is some concern that HBV may be the cause of:

  • Persistent wheezing disorder in children.
  • Asthma: multiple attacks of acute exacerbation.
  • Frequent otitis media.
  • Repeated lower respiratory tract infections.

The reports are compelling, but this discovery is still in its infancy and more studies are needed to confirm the role of the human mouth virus in chronic airway inflammation.

Conclusion and future challenge

Based on current data, the pathogenic roles of the various HBV genotypes in respiratory tract diseases and gastrointestinal infections remain unresolved.

It is possible that the virus is both a passenger and a pathogen causing acute respiratory and gastrointestinal diseases.

The contradictory ideas about this pathogenic role stem mainly from the fact that Koch’s revised postulates cannot be applied to HBV, because to date there is no effective method for the culture of viruses or an animal model of infection.

Furthermore, several studies have indicated that HBV requires the presence of other agents to carry out infection.

Recent studies have shown that HAE-ALI HBV 1 infection induces a DNA damage response that facilitates amplification of the viral genome.

However, more research is needed to develop suitable cell lines and animal models for viral replication in order to obtain more evidence to better understand the natural course of HBV infection.

In this regard, simpler culture methods and infectious clones should be available, as genomic analysis of HBV is difficult for this reason alone.

Despite a relatively substantial amount of knowledge on the molecular basis of the HBV life cycle, the function of various HBV proteins still requires further investigation.

For example, only recently were three novel NS proteins (NS2, NS3, and NS4) identified; Among these, only one NS protein is critical for virus replication in the epithelium of polarized human bronchial airways.

The role of the other proteins remains quite uncertain.

Most of the studies to date have been conducted on the HBV genotype 1, while little information is available on the other agents.

It should be noted that the presence of HBV 2, HBV and HBV 4 in the respiratory tract should be further investigated, as well as their phylogenetic relationships.

Our phylogenetic analysis suggests, as shown by other authors, that HBV 3 may result from the recombination of HBV 1 and HBV 2; but, it can also be a hybrid of HBoV1, with a common ancestor of HBV 2 and HBV 4.

In this regard, it would be appropriate for future studies to evaluate more and at the same time (possibly all) genotypes and genes.

HBV subtypes have been found throughout the world, without regional, geographic, or border restrictions. HBV 1 is associated with pediatric respiratory diseases, but also with gastrointestinal symptoms.

HBV 2, HBV 3, and HBV 4 are most frequently detected in stool samples and appear to be enteric. Also, the most typical age for HBV infection is <2 years of age; it has only rarely been found in adults and the elderly.

In this regard, clinical studies would be useful to characterize the pathogenesis of the disease and to understand immunity in the diverse populations represented by infants, the elderly, or immunocompromised individuals who respond to HBV infection.

There is also a need to optimize commercial diagnostic reagents and methods for HBV identification.

In general, the detection of HBoV is carried out mainly through molecular techniques (ie PCR and RT-PCR); only rarely is it performed with serological methods (ie, ELISA, EIA, Western blotting, and immunofluorescence), due to the lack of commercial kits.

Furthermore, the development of new sequence-independent amplification techniques combined with next-generation sequencing platforms is worthy of achieving rapid and simultaneous detection of numerous pathogens.

Finally, if the pathogenic role of HBV is to be confirmed, the development of an effective vaccine to control the spread of the infection should be of primary importance.

In the hope of achieving this goal, many studies have been conducted on HBV viral capsid proteins. Previous research studies have confirmed that VLPs can be used as safe and effective vaccines.

Recently, in vitro studies have shown that HBV VP2 VLPs have good immunogenicity and studies in mice have shown that they can induce strong humoral and cellular immune responses, indicating their promise as candidate proteins for the HBV vaccine.

The most recent data suggest that the creation of non-replicating infectious HBV 1 mutants may represent a new approach to HBV vaccine development.

In conclusion, a better understanding of the natural course of HBV infection, the implementation of experimental systems to analyze the replication cycle in more detail, and the development of specific therapies are important and urgent needs.