key: cord-0003394-bi0tai8t
authors: Rikhotso, Mpumelelo Casper; Kabue, Jean Pierre; Ledwaba, Solanka Ellen; Traoré, Afsatou Ndama; Potgieter, Natasha
title: Prevalence of Human Bocavirus in Africa and Other Developing Countries between 2005 and 2016: A Potential Emerging Viral Pathogen for Diarrhea
date: 2018-09-12
journal: J Trop Med
DOI: 10.1155/2018/7875482
sha: 6ed9a8fa706f8553d2111e38145c95990b26ba9b
doc_id: 3394
cord_uid: bi0tai8t

BACKGROUND: Human Bocavirus (HBoV) is an emerging virus discovered in 2005 from individuals suffering gastroenteritis and respiratory tract infections. Numerous studies related to the epidemiology and pathogenesis of HBoV have been conducted worldwide. This review reports on HBoV studies in individuals with acute gastroenteritis, with and without respiratory tract infections in Africa between 2005 and 2016. MATERIAL AND METHOD: The search engines of PubMed, Google Scholar, and Embase database for published articles of HBoV were used to obtain data between 2005 and 2016. The search words included were as follows: studies performed in Africa or/other developing countries or/worldwide; studies for the detection of HBoV in patients with/without diarrhea and respiratory tract infection; studies using standardized laboratory techniques for detection. RESULTS: The search yielded a total of 756 publications with 70 studies meeting the inclusion criteria. Studies included children and individuals of all age groups. HBoV prevalence in Africa was 13% in individuals suffering gastroenteritis with/without respiratory tract infection. CONCLUSION: Reports suggest that HBoV infections are increasingly being recognized worldwide. Therefore, surveillance of individuals suffering from infections in Africa is required to monitor the prevalence of HBoV and help understand the role of HBoV in individuals suffering from gastroenteritis with/without respiratory tract infection.

Diarrhea is a leading cause of morbidity and mortality in children worldwide [1, 2] . Diarrhea is the third major cause of childhood mortality in children less than 5 years of age especially in Africa and developing countries [3] [4] [5] . The modes of transmission include ingestion of contaminated food or water (e.g., via flies, inadequate sanitation facilities, sewage and water treatment systems, and cleaning food with contaminated water), direct contact with infected feces (fecaloral route), person-to-person contact, and poor personal hygiene [6, 7] .

According to WHO [1] , approximately 90% of the estimated 2.2 million of deaths caused by diarrheal infections in children less than 5 years of age are related to poor sanitation and hygiene behaviors worldwide. While the mortality due to diarrheal diseases has declined significantly in children over the past twenty years in developed countries [8, 9] , the incidence of childhood diarrhea in developing countries has not decreased [1, 2] . Those who survive these illnesses have repeated infections by enteric pathogens which remains a critical factor leading to serious lifelong health consequences [10] and eventually result in death [11] . Viruses are recognized as major cause of gastroenteritis, particularly in children, and the number of viral agents associated with diarrheal disease in humans has increased progressively. Viruses such as rotavirus, norovirus, astrovirus, and adenovirus that cause diarrhea have been reported worldwide [11] .

The Human Bocavirus (HBoV) is a viral agent that has been reported worldwide in various studies as a potential cause of diarrhea outbreaks [5, [12] [13] [14] [15] [16] [17] [18] . The HBoV is a member of the Parvoviridae family, Parvovirinae subfamily, and the genus of Bocavirus [19] [20] [21] . The family Parvoviridae includes small, nonenveloped, icosahedral viruses with 5.3 kb single stranded DNA genome containing three open reading frames (ORFs); the first ORF, at the 5 end, encodes NS1, a nonstructural protein [22] . The second ORF encodes NP1, a second nonstructural protein. The third ORF, at the 3 end, encodes the two structural capsid viral proteins (VPs), VP1 and VP2 [23, 24] . There are currently four Bocavirus species identified worldwide, namely, HBoV1, HBoV2, HboV3, and HBoV4 [5, [25] [26] [27] [28] . HBoV was first discovered in 2005 in children with acute respiratory tract infection [28] . In 2007, HBoV was detected in children suffering from gastroenteritis with and without symptoms of respiratory tract infections [14, [29] [30] [31] . Primary infection with HBoV occurs early in life in children between 6-24 months of age [32] [33] [34] ; however, older children and adults can also be infected [28, 35] . Currently there is no specific approved treatment or vaccine for HBoV infection [25, 36, 37] . Since its discovery, the virus was mainly associated with respiratory tract infections, but recent studies have revealed the involvement of the virus in gastroenteritis.

These studies indicate that only HBoV2, HBoV3, and HBoV4 strains of the virus are mainly involved in gastroenteritis [37] [38] [39] . Currently, there is limited data on ELISA method for the detection of the virus. HBoV detection has been done by conventional PCR [17, 28, 40, 41] and real-time PCR [42] [43] [44] [45] . While HBoV epidemiological studies have shown evidence for widespread exposure to the virus, the causative role of HBoV in respiratory tract disease and gastroenteritis is still under investigation [46] . Proven evidence is difficult to obtain without an in vitro culture system and animal model [28, [47] [48] [49] .

The prevalence of HBoV has been reported in Europe [50, 51] , America [17, 41] , Asia [34, 52] , Australia [40, 53] , Africa [54] , and the Middle East [18] , ranging from 1.5% to 19.3% [17, 55] . This review is a summary of reported HBoV studies in individuals with acute gastroenteritis, with and without respiratory tract infections looking specifically to studies in Africa to determine the role of HBoV in diarrheal outbreaks.

A literature search of selected studies that investigated HBoV in Africa, in other developing countries and worldwide was performed using the following terms: Human + Bocavirus + Africa + Developing countries + Worldwide on PubMed, Google scholar and Embase. This search yielded 756 publications (Figure 1 ). The first search was performed for HBoV + Africa, the second search was HBoV + other developing countries, and the third search was HBoV + worldwide. Keywords used included Human Bocavirus, Bocavirus, and Human parvovirus combined for each (Africa; Developing country; Worldwide). To avoid leaving out any studies not found in major scientific databases, Google search was also used. After reviewing each article, studies were selected if they met the following inclusion criteria: (ii) Studies for the detection of HBoV in patients with or without diarrhea and respiratory tract symptoms. Diarrhea defined as the passage of loose or watery stools, at least three times in a 24-h period [56] .

(iii) Studies using standardized laboratory techniques for detection of HBoV including PCR, real-time-PCR, and Multiplex PCR (m-PCR).

Information extracted from the inclusion studies included country where study was done, time period of study, age range of participants, study setting (rural/urban/periurban), sampled population (number of included samples), method used for detection, clinical symptoms, sample type, and HBoV subtype.

All analysis were conducted using R programming environment for data analysis and graphics Version 3.5.0 [57] to calculate random and fixed effects. Function "rma" from the package Metafor [58] was used to calculate heterogeneity between studies and generate a forest plot. Heterogeneity was assessed by Cochran's Q test.

Between Table 1) . The most reported HBoV subtype was HBoV1 (100%; 70/70), followed by HBoV2 (16%; 11/70), HBoV3 (13%; 9/70), and HBoV4 (7%; 5/70) (Table 1) . A total of 54% (36/67) studies were done on samples collected from nasal swabs, 7% (5/67) were done on samples collected from throat swabs, 22% (15/67) were done on stool samples, 4% (3/67) were combined nasal/throat samples, 3% (2/67) were combined stool/nasal samples, 6% (4/67) were combination of nasal/ stool/serum samples, and 3% (3/67) were a combination of nasal/serum samples.

Meta-analysis was done to provide transparent, objective, and replicable summaries of the study findings. From all the 70 studies, 66 had sufficient information to enable statistical analysis. As shown in Figure 2 with the dispersion in study prevalence, there was a low heterogeneity among the studies (Cochran Q = 12.2800 [df = 65] P-Val = 1). Apart from the observed increase in the prevalence of HBoV, none of the other drivers (including age, setting, symptoms, method of detection, and hospitalization) achieved statistical significance. The test for overall effect was Z = 13.29 (P<0.0001) which was highly significant in the findings.

Ten studies were from other developing countries of which eight studies (80%) reported on patients suffering from respiratory tract infection and two studies (20%) reported on patients suffering from diarrheal disease. All ten of the studies focused only on children (100%; 10/10) ( Table 2 ). All studies in other developing countries worked on hospitalized patients ( Table 2) . A total of 70% (7/10) of the studies collected nasal swabs, 20% collected throat swabs, and 20% of the studies collected stool samples. The most sampled population was children ≤ 6 years of age (Table 2) . Majority 60% (6/10) were done in urban setting in other developing countries while 40% (4/10) were done in rural settings. Eight (80%) of the studies reported on patients suffering from respiratory tract infections (Table 2 ). In other developing countries, HBoV was reported in Argentina 10% (1/10), Cambodia 10% (1/10), China 40% (4/10), India 10% (1/10), Jordan 10%(1/10), and the Philippines 10%(1/10).

In Africa, the majority of studies (82%; 9/11) were done in urban settings while 18% (2/11) were done in rural settings. Ten (91%) of the studies reported on patients suffering from respiratory tract infections and one study (9%) reported on patients suffering from gastroenteritis. In these studies, a total of 383 (10.4%) samples tested positive for HBoV (Table 3) . More studies reported HBoV in children less than five years of age (54%; 6/11) compared to children above the age of 5 and adults 45% (5/11) ( Table 3 ).

Countries that reported on HBoV in Africa included Kenya 18% (2/11), South Africa 36% (4/11), Egypt 18% (2/11), Cameroon 9% (1/11), and Senegal 18% (2/11). Five of the 11 studies in Africa focused on hospitalized patients and 36% (4/11) studies focused on outpatients, while 18% (2/11) studies focused on both hospitalized and outpatients. Eight (73%; 8/11) of the studies in Africa collected nasal swabs, two studies 18% (2/11) collected throat swabs, and one (9%; 1/11) study collected stool samples.

The prevalence of HBoV in Africa was 13% in individuals suffering from gastroenteritis with and without respiratory tract symptoms. The high detection rate of HBoV in Africa was consistent with the global increase of HBoV in children less than 5 years of age [4, 59] . Children of all age group are most likely to experience HBoV infection as a result of poor sanitation and hygiene practices [59] . The most predominant HBoV subtype identified in Africa was HBoV1, which was detected in all the studies. Only one study (9%), from Kenya detected all subtypes (HBoV1-4) from children of all age group (Table 3) . Not all the studies tested for all HBoV subtypes; this may be due to the fact that other HBoV subtypes have just been recently discovered compared to HBoV1 [37] . The most predominant HBoV subtype identified in other developing countries was HBoV1, which was isolated in all the studies. Only 10% (1/10) of the studies from china detected HBoV2 in the study population ( Table 2) .

The results in Africa indicated that HBoV in children less than five years of age was high, 54% (6/11) compared to children above 5 years of age and adults 45% (5/11) ( Table 3 ). Schildgen and colleagues [60] showed that all age groups can be affected by HBoV, although severe infections requiring hospitalization occur primarily in patients with an underlying disease and children under 5 years of age [61] [62] [63] [64] . Journal of Tropical Medicine 7 Journal of Tropical Medicine 9 Severe clinical cases (such as destruction of the epithelium of the respiratory system) have been described in children [61, [64] [65] [66] and adults with immunodeficiency [64] and other risk groups [67] . Studies in Africa (13%; 9/70) were mostly done in urban setting compared to other developing countries/worldwide (87%; 61/70) (Tables 1, 2, and 3 ). This could be due to the lack of laboratory resource capacity and technology for the detection of HBoV in rural settings.

The methods used for detecting HBoV have been conventional PCR [17, 28, 40, 41, 45, 53, 64] and real-time PCR [42-45, 54, 68] , due to the limited success of serological and viral culture techniques. Real-time PCR is more sensitive and offers greater sensitivity, increased specificity with the addition of oligoprobes, and the added benefit of a closed detection system, reducing the likelihood of false positive results due to contamination with amplicon [33] . In Africa, 63% (7/11) of studies used conventional PCR for detection, 27% (3/11) used real-time PCR, and 9% (1/11) used Multiplex PCR which is also conventional PCR (Table 3 ).

In all eleven African studies, HBoV1 was detected (Table 3) , similarly in other developing countries HBoV1 was detected in all the studies. HBoV Subtype 1 is mainly associated with respiratory diseases but can also be found in stool samples from patients suffering from diarrhea. Previous studies have reported prevalence of HBoV in symptomatic patients 1.5-16% worldwide [69, 70] . Several studies have isolated HBoV from children with respiratory tract infection worldwide, and the prevalence of HBoV in these children was 1.5%-19% [32, 33, 35] .

The reports on HBoV in Africa, other developing countries, and worldwide in individuals suffering from respiratory tract infection 78% (55/70) were higher compared to those suffering from gastroenteritis 21% (15/70) (Tables 1, 2, and  3 ). This could be due to the fact that most studies focused on HBoV in respiratory tract infection since its discovery in 2005 [28, 33, 36, 71] . However recent studies are increasingly detecting HBoV in individuals suffering from diarrheal diseases due to the presence of the virus in stool samples of individuals suffering from gastroenteritis [37, [72] [73] [74] .

Although the number of studies in Africa is limited, the HBoV prevalence rate of 13% indicates that this virus is one of the emerging viral agents in those suffering from diarrhea with and without respiratory tract infections. Currently there is no available reporting system for HBoV infection in the primary healthcare systems in Africa, suggesting that diarrheal cases with and without respiratory tract infection are likely to be underreported [47] . The high frequency of HBoV in children raises a potential health risk as these children may act as reservoir for other emerging epidemic HBoV strains [27, 37, 75 ].

More studies are required in Africa, especially in rural settings to monitor the prevalence of HBoV and help understand the role of HBoV in individuals suffering from gastroenteritis with/without respiratory tract infection. HBoV infections are likely to be underreported in Africa considering the costs of testing for the virus. This review was done to shed light on HBoV and its possible role in diarrheal incidence.

The authors declare no conflicts of interest.

Global, regional and national causes of child mortality: an update systematic analysis for 2010 with time trends since

Molecular detection and phylogenetic analysis of Kenyan human bocavirus isolates

Sentinel surveillance for influenza in Senegal

Newly identified respiratory viruses in children with asthma exacerbation not requiring admission to hospital

Climate change and waterborne diarrhoea in northern India: Impacts and adaptation strategies

Why Children Are Still Dying and What Can Be Done, United Nations Children's Fund

A novel primer set for improved direct gene sequencing of human bocavirus genotype-1 from clinical samples

The epidemiology of enteric caliciviruses from humans: a reassessment using new diagnostics

Managing acute gastroenteritis among children; oral rehydration, maintenance, and nutritional therapy

The impoverished gut-a triple burden of diarrhoea, stunting and chronic disease

Risk factors for hospitalization with lower respiratory tract infections in children in rural Alaska

Human bocavirus detection in nasopharyngeal aspirates of children without clinical symptoms of respiratory infection

Human bocavirus, a respiratory and enteric virus

Norovirus detection and genotyping for children with gastroenteritis, Brazil

Rotavirus surveillance in the city of Rio de Janeiro-Brazil during 2000-2004: Detection of unusual strains with G8F or G10P specifities

Human bocavirus infection, Canada

Human bocavirus infection among children

Humoral immune response against human bocavirus VP2 virus-like particles

Complete coding sequences and phylogenetic analysis of human bocavirus (HBoV)

Human bocavirus: developing evidence for pathogenicity

Human bocavirus capsid structure: Insights into the structural repertoire of the Parvoviridae

Human bocavirus NP1 inhibits IFN-production by blocking association of IFN regulatory factor 3 with IFNB promoter

Comparison of thcell immunity against human bocavirus and parvovirus b19: proliferation and cytokine responses are similar in magnitude but more closely interrelated with human bocavirus

A novel bocavirus associated with acute gastroenteritis in Australian children

Detection of human bocavirus in respiratory, fecal, and blood samples by real-time PCR

Real-time quantitative PCR detection of four human bocaviruses

Cloning of a human parvovirus by molecular screening of respiratory tract samples

High human bocavirus viral load is associated with disease severity in children under five years of age

Human bocavirus in Italian patients with respiratory diseases

Frequent detection of bocavirus DNA in German children with respiratory tract infections

Human bocavirus infection in young children with acute respiratory tract infection in Lanzhou, China

Human bocavirus infection in children with acute gastroenteritis and healthy controls

Detection of human Bocavirus in Japanese children with lower respiratory tract infections

The human bocaviruses: a review and discussion of their role in infection

Circulating of human bocavirus 1, 2, 3, and 4 in pediatric patients with acute gastroenteritis in Thailand

No efficacy of prednisolone in acute wheezing associated with human bocavirus infection

High prevalence of human bocavirus 2 and its role in childhood acute gastroenteritis in China

Human bocavirus in children

Frequent detection of human rhinoviruses, paramyxoviruses, coronaviruses, and bocavirus during acute respiratory tract infections

Human bocavirus infection in young children in the United States: Molecular epidemiological profile and clinical characteristics of a newly emerging respiratory virus

Identification of a third human polyomavirus

Impact on respiratory tract infections of heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 11 months of age

The association of newly identified respiratory viruses with lower respiratory tract infections in Korean children

Epidemiological profile and clinical associations of human bocavirus and other human parvoviruses

Genomic features of the human bocaviruses

Seroepidemiology of human bocavirus infection in Jamaica

Bocavirus episome in infected human tissue contains Non-Identical termini

Characterization of the gene expression profile of human bocavirus

Isolation of human bocavirus from Swiss infants with respiratory infections

Human bocavirus in French children

Quantification of human bocavirus in lower respiratory tract infections in China

Evidence of human coronavirus HKU1 and human bocavirus in Australian children

Human bocavirus in hospitalized children, South Africa

Frequent detection of viral coinfection in children hospitalized with acute respiratory tract infection using a real-time polymerase chain reaction

Treatment of diarrhea: a manual for physicians and senior health workers

Programming language and free software environment for statistical computing and graphics (Statistical analysis)

Package "metagen

Human bocavirus infection in children with acute respiratory infection in

Human bocavirus: lessons learned to date

Fatal type 7 adenovirus associated with human bocavirus infection in a healthy child

Etiology of bronchiolitis in a hospitalized pediatric population: Prospective multicenter study

Clinical characteristics of human bocavirus infections compared with other respiratory viruses in Spanish children

Severe pneumonia and human bocavirus in adult

Human bocavirus: prevalence and clinical spectrum at a children's hospital

Frequent and prolonged shedding of bocavirus in young children attending daycare

Low prevalence of human metapneumovirus and human bocavirus in adult immunocompromised high risk patients suspected to suffer from Pneumocystis pneumonia

Human bocavirus infection, People's Republic of China

Human bocavirus amongst an all-ages population hospitalised with acute lower respiratory infections in Cambodia

Viral etiologies of acute respiratory infections among hospitalized vietnamese children in Ho Chi Minh City

Human bocavirus infection in children with acute gastroenteritis in Japan and Thailand

Detection of human bocaviruses 1, 2 and 3 in Irish children presenting with gastroenteritis

Detection of human bocaviruses 1 to 4 from nasopharyngeal swab samples collected from patients with respiratory tract infections

Human bocaviruses are highly diverse, dispersed, recombination prone, and prevalent in enteric infections

PCR improves diagnostic yield from lung aspiration in malawian children with radiologically confirmed pneumonia

Human bocavirus respiratory infection in infants in Córdoba, Argentina

Frequency of human bocavirus (HBoV) infection among children with febrile respiratory symptoms in Argentina, Nicaragua and Peru

Human bocavirus 1 and 3 infection in children with acute gastroenteritis in Brazil

Hospitalacquired human bocavirus in infants

Hypertrophic adenoid is a major infection site of human bocavirus 1

High rates of detection of respiratory viruses in tonsillar tissues from children with chronic adenotonsillar disease

Detection of human bocavirus mRNA in respiratory secretions correlates with high viral load and concurrent diarrhea

Viral and atypical bacterial detection in acute respiratory infection in children under five years

Ocurrence of human bocavirus associated with acute respiratory infections in children up to 2 years old in the city of belém, Pará State, Brazil

Respiratory virus infections in hospitalized children and adults in Lao PDR

Viral etiology of severe acute respiratory infections in hospitalized children in Cameroon

Viral etiologies of hospitalized acute lower respiratory infection patients in China

Clinical and molecular epidemiology of human bocavirus in respiratory and fecal samples from children in Hong Kong

Novel human bocavirus in children with acute respiratory tract infection

Molecular identification and epidemiological features of human adenoviruses associated with acute respiratory infections in hospitalized children in Southern China

A two-tube multiplex reverse transcription PCR assay for simultaneous detection of viral and bacterial pathogens of infectious diarrhea

New epidemiological and clinical signatures of 18 pathogens from respiratory tract infections based on a 5-year study

Epidemiology of acute respiratory infections in children in Guangzhou: A three-year study

Prevalence and clinical profile of human bocavirus in children with acute gastroenteritis in Chengdu

Human bocavirus among viral causes of infantile gastroenteritis

Serodiagnosis of human bocavirus infection

Evaluation of four commercial multiplex molecular tests for the diagnosis of acute respiratory infections

Real-time PCR for diagnosis of human bocavirus infections and phylogenetic analysis

Real-time PCR assays for detection of bocavirus in human specimens

Acute nonbacterial gastroenteritis in hospitalized children: a cross sectional study

Human Bocavirus in Iranian children with acute gastroenteritis

Prevalence and seasonal distribution of respiratory viruses during the 2014 -2015 season in Istanbul

The human bocavirus role in acute respiratory tract infections of pediatric patients as defined by viral load quantification

Human bocavirus infection in hospitalized children in Italy

Molecular detection of gastrointestinal viral infections in hospitalized patients

Molecular detection of human metapneumovirus and human bocavirus on oropharyngeal swabs collected from young children with acute respiratory tract infections from rural and peri-urban communities in South India

Human bocavirus in Jordan: Prevalence and clinical symptoms in hospitalised paediatric patients and molecular virus characterisation

Molecular epidemiology and disease severity of respiratory syncytial virus in relation to other potential pathogens in children hospitalized with acute respiratory infection in Jordan

Distinctive clinical features of human bocavirus in children younger than 2 years

Human bocaviruses are not significantly associated with gastroenteritis: Results of retesting archive DNA from a case control study in the UK

First detected human bocavirus in a Malaysian child with pneumonia and pre-existing asthma: A case report

Human bocavirus in febrile children consulting a GP service in the Netherlands

A newly identified bocavirus species in human stool

Respiratory viruses from hospitalized children with severe pneumonia in the Philippines

Respiratory viruses associated with patients older than 50 years presenting with ILI in Senegal

Clinical epidemiology of bocavirus, rhinovirus, two polyomaviruses and four coronaviruses in HIV-infected and HIV-uninfected South African children

Role of human metapneumovirus, human coronavirus NL63 and human bocavirus in infants and young children with acute wheezing

Bacterial and respiratory viral interactions in the etiology of acute otitis media in HIV-infected and HIV-uninfected South African Children

Human bocavirus as an important cause of respiratory tract infection in Taiwanese children

Detection of human bocavirus DNA by multiplex PCR analysis: Postmortem case report

Severe lower respiratory tract infection in infants and toddlers from a nonaffluent population: viral etiology and co-detection as risk factors

The authors would like to express their gratitude to the library staff members of the University of Venda who provided assistance for this review. This study was done through funding from the Director of Research and Innovation, University of Venda, Project no. SMNS/17/MBY/03.