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Abstract

The emergence of the COVID-19 pandemic highlighted the importance of studying newly emerging viruses that cause respiratory illnesses. Human bocavirus (HBoV) is one of the relatively newly discovered viruses that has been detected worldwide and causes respiratory and gastrointestinal infections, mainly in pediatric patients. However, little is known about the pathogenicity and evolution of HBoV. This systematic review was initiated to clarify the prevalence and circulating genotypes of HBoV in both respiratory and stool samples from patients of all age groups in the Middle East and North Africa (MENA) from 2005 to February 2021. We performed an electronic search through Science Direct, Scopus, PubMed, Mendeley and Cochrane Library databases. We included all studies reporting the detection rate of HBoV in the MENA region. Data were extracted, and the quality of the included articles was assessed. We included articles containing data on HBoV only or with other respiratory or gastrointestinal viral infections. Review articles, case studies, and animal and environmental studies were excluded. The final number of articles included in this study was 65 articles. The results showed that the HBoV prevalence in children was the lowest in Iran (0%) and the highest in Egypt (56.8%). In adults, the lowest and the highest prevalence were reported in Iran, with values of 0% and 6.6%, respectively. Regarding the respiratory cases, our findings revealed no significant difference between HBoV prevalence among the tested categories (p-value = 0.998). The present study has shown that HBoV is common in children and adults in the MENA region. This systematic review highlights the need for more data on the role of coinfection of HBoV and other viruses, for instance, SARS-CoV-2 in children with acute bronchiolitis.

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1. Introduction

Human bocavirus (HBoV) is a parvovirus reported for the first time in 2005 [1]. Since then, an increasing number of reports have emerged indicating the common presence of the virus in the respiratory and gastrointestinal samples. HBoV is known to cause viral respiratory and gastrointestinal tract infections [1,2]. However, the pathogenicity of the virus is not fully understood [3,4]. As with other viruses that cause respiratory tract infections, HBoV can occur during any time of the year, with the highest incidence rate during winter and spring [5,6]. Although HBoV has been found in individuals of all ages, it was mainly reported in infants aged 6–24 months [4,5].

HBoV is a small non-enveloped single-stranded DNA virus with a genome size of 5300 nucleotides. The name Bocavirus was derived after the phylogenetic analysis of the HBoV genome, which showed a close relation to bovine parvovirus (BPV1) and minute virus of canines (MVC). HBoV belongs to the family Parvoviridae, subfamily Parvovirinae and genus Bocavirus. There are four genotypes that belong to the Bocavirus genus. The first genotype was named HBoV1, and was predominantly reported in respiratory samples [7]. The others, named HBoV2, 3 and 4, were reported in the stool samples of gastroenteritis patients [8].

Globally, the total prevalence of HBoV was estimated at around 6.0% [3]. Death cases due to HBoV infections have been reported [9,10,11]. However, there is no definite death rate. The Middle East and North Africa (MENA) region is a term that represents a group of twenty-one countries found in Asia (Bahrain, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, Syria, Turkey, United Arab Emirates, Palestine and Yemen) and Africa (Algeria, Egypt, Libya, Morocco, Sudan and Tunisia) (https://istizada.com/mena-region/, accessed on 16 January 2021) (Figure 1). Only 14 countries reported the prevalence of HBoV in the MENA region. On the other hand, a lack of reported data was noticed in several countries (Bahrain, Syria, Palestine, Yemen, Algeria, Libya and Morocco) due to lack of knowledge, awareness and attitude of physicians, wars, conflicts, civil revolutions and low scientific research output. The aim of this systematic review was to investigate the prevalence of HBoV and its distribution in the MENA region. Data included patients of all age groups, mainly children, with acute respiratory and gastrointestinal infections, including pilgrims returning from Hajj and Umrah and suffering from acquired acute respiratory tract illness (ARI).

2. Methods

2.1. Search Strategy and Selection Criteria

This systematic literature review involves all published journal articles and preprints that reported HBoV prevalence and genotypes in the Middle East and North Africa (MENA) region between 2005 and February 2021. Five databases were searched (Science Direct, Scopus, PubMed, Mendeley and Cochrane Library) by using (“boca*” OR “bocavirus” OR “boca virus”) AND (“gastro*” OR “genotype” OR “epidemiology” OR “resp*” OR “prevalence” OR “type”) AND (“The Middle East” OR “North Africa” OR “The Middle East and North Africa” OR “The Middle East & North Africa” OR “MENA” OR “Algeria” OR “Bahrain” OR “Djibouti” OR “Egypt” OR “Iran” OR “Iraq” OR “Jordan” OR “Kuwait” OR “Lebanon” OR “Libya” OR “Morocco” OR “Occupied Palestinian Territories” OR “Oman” OR “Palestine” OR “Qatar” OR “Saudi Arabia” OR “KSA” OR “Somalia” OR “Sudan” OR “Syria” OR “Tunisia” OR “UAE” OR “The United Arab Emirates” OR “Yemen”) as a search strategy. The eligible articles were screened for both the titles and abstracts. The studies involved in this systematic review were selected based on the following criteria: (1) the published articles contain data on HBoV only or with other respiratory or gastrointestinal viral infections from 2005 to February 2021, (2) the studied population in the article is patients residing in, or having acquired infection from, the MENA region. Review articles, case studies, and animal and environmental studies were excluded.

2.2. Data Collection and Data Adjustment

Following the research strategy, a total of 265 articles were identified as follows: 117 articles from PubMed, 73 from Mendeley, 60 from Scopus, eight from Science Direct and seven articles from Cochran. The number of records after deduplication was 175, 88 articles were excluded due to their titles, 11 articles were excluded due to their abstracts and 12 articles were excluded after full-text article screening. The final number of articles included in this study was 65 articles (Figure 2).

The data collection sheet was designed to extract data from the selected articles at a 95% confidence interval. The prevalence data were extracted and arranged according to the country and year of sample collection and were reported as percentages. Data of respiratory records were compared by Fisher’s exact test, and p-values were calculated in IBM SPSS statistics version 28 by using the Chi-square test to identify associations.

The summary of individual study parameters was prepared using Microsoft Excel. A mean percentage prevalence was taken if more than one prevalence study was reported from the same country. Prevalence charts were produced for both respiratory and gastrointestinal samples.

3. Results

In total, 142,748 patients were reported in sixty-five studies, and 5622 (3.94%) were positive for infection. All those studies reported the prevalence of HBoV in the MENA from 2005 to February 2021 (Table 1). A mean percentage prevalence was calculated for each country for both respiratory and gastrointestinal samples. The prevalence charts were constructed for both respiratory (Figure 3) and gastrointestinal samples (Figure 4).

This systematic review reports the prevalence of HBoV in the MENA region among different tested categories including various age groups (pediatric, children, adults and elderly), COVID-19 cases, pilgrims, health care providers, blood donors and patients with colorectal cancer. Concerning the respiratory cases, our findings revealed no significant differences between HBoV prevalence values among the tested categories (p-value = 0.998).

The study design for almost all of the included studies was a cross-sectional study that aligns with the prevalence determination. In addition, a pilot study, case-control and cohort studies were included in this systematic review. The different study designs can explain the heterogeneity of the sample size.

All included studies used valid assay procedures for the detection of HBoV. The most commonly used method is real-time polymerase chain reaction (RT-PCR). Samples from the upper (nasopharyngeal aspirates, nasopharyngeal swabs or oropharyngeal swab), middle (tracheal aspirate) and lower respiratory tract (Broncho alveolar lavage) were examined for patients with respiratory tract infection. Stool was the specimen of choice for patients with gastroenteritis.

Surgically excised specimens were used to screen human bocavirus in colorectal cancer patients. Whole blood samples from blood donors were screened for HBoV to investigate the possibility of parenteral transmission.

4. Discussion

In the MENA Region, several reports studied the prevalence of HBoV among hospitalized children and adults suffering respiratory tract infections and whether HBoV was the causal agent [27,41]. At the same time, others investigated the HBoV prevalence in patients with gastroenteritis [14,24].

The results showed that the prevalence of HBoV varied from one country to another. The HBoV prevalence, in cases of respiratory tract infection in children, ranged from 0% in Iran to 56.8% in Egypt [16,30]. In adults, the highest prevalence (6.6%) was observed in Iran [27]. Few studies have focused on HBoV isolated from stool specimens to recognize the role of HBoV in gastroenteritis. Only nine studies were found in the MENA, five of them from Iran, and the others were conducted on populations in Egypt, Kuwait, Sudan and Tunisia. Among these studies, the lowest prevalence was reported in Sudan in 2018 (1.10%) [61], while the highest prevalence (33%) was reported in Tunisia [62]. Several factors affect the variations in the prevalence of the virus in these populations, including the geographical location of the country, the clinical diagnosis of the studied population, the type of sample, the method used for detection of the virus, the age group of the examined population and the outbreak season of the virus.

Abdel-Moneim et al. (2016) used newly developed primers to increase the sensitivity of the PCR test for HBoV detection. Using these novel primers, the prevalence of HBoV was 56.8%, which significantly differs from previous and further studies conducted in Egypt, which found prevalence values of 22%, 10% and 18.2% respectively [12,13,17]. Abdel-Moneim et al. explained that the high rate of prevalence of HBoV-1 was reported because of a potential nosocomial pathogen among pediatric care units. This explanation was verified by Cabral et al. in (2021) after he demonstrated that bocavirus is one of the airborne respiratory conditions transmitted during the analysis of the air in pediatric emergency department waiting rooms [75]. Therefore, early diagnosis of HBoV infection in the initial hospitalization time may decrease the spread of the viral infection, especially in pediatric units [47]. Moreover, unlike other respiratory viruses, HBoV can be detected in the serum and whole blood samples of patients suffering from viremia [56].

In Egypt, Abdel-Moneim et al. (2016) studied the presence of HBoV in colorectal cancer patients and found that among one hundred and one patients, twenty-four of them (23.8%) were positive for HBoV [15]. Moreover, Niya et al. (2018) used a case versus control population to detect the presence of the HBoV genome in colorectal cancer patients’ tissue and compared the result with matched healthy control group tissue; HBoV was detected in one patient from each group, with a total prevalence of 1.3% [31].

Several studies have reported the spreading of HBoV among pilgrims during Hajj and Umrah, as mass gathering aids in the transmission of respiratory diseases. The studies concluded that raising awareness among pilgrims of the importance of following public health precautions, such as wearing masks and undergoing vaccination, significantly reduces the transmission of respiratory pathogens [57,60,70].

Currently, four genotypes have been identified worldwide (HBoV1, HBoV2, HBoV3 and HBoV4). In the MENA Region, HBoV1 is the most prominent reported genotype and is mainly associated with respiratory diseases [20,28]. However, HBoV1 was rarely detected in stool samples [25]. Genotypes 2, 3 and 4 were reported in cases of acute gastroenteritis [25,62].

HBoV is detected more frequently with other viruses in the respiratory and gastrointestinal tract (Table 2). HBoV co-infection is present at a high rate among the tested samples, especially with respiratory syncytial virus (RSV) [13,32,41], which is the most prominent virus that causes respiratory illness.

However, there is a conflict regarding the role of HBoV in cases of co-infection. Some studies reported no differences in clinical severity between patients hospitalized with a single infection (sole virus) and those with viral co-infection [13,47]. Others proved that more disease severity was associated with a high viral load detected in a single infection [18,76].

5. Conclusions

This systematic review provides a clear summary of the existing knowledge about the prevalence of HBoV infection in the MENA region. The data presented show that HBoV infection is common in children admitted to hospitals and should be screened for as a part of the standard diagnostic panels. This systematic review also highlights the importance of studying the presence of this virus alone or in association with other viruses and stresses the need for further research on the pathogenicity and genomic variation of HBoV.

Author Contributions

Supervision: L.A.; Data collection: R.A. and H.H.; Data analysis and interpretation: R.A., H.H. and L.A.; Prepared tables: R.A. and H.H.; Figure preparation: R.A. and H.H.; Statistical analysis: H.H.; Writing—original draft: R.A., H.H. and L.A.; Writing—review and editing: all authors. All authors have read and agreed to the published version of the manuscript.

Funding

This study did not receive any funding.

Conflicts of Interest

We declare that we have no competing interests nor conflicts of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures and Tables
View Image - Figure 1. The Middle East and North Africa region (MENA) (https://istizada.com/mena-region/ (assessed on 16 January 2021).

Figure 1. The Middle East and North Africa region (MENA) (https://istizada.com/mena-region/ (assessed on 16 January 2021).

View Image - Figure 2. Flow chart of the study selection protocol.

Figure 2. Flow chart of the study selection protocol.

View Image - Figure 3. The prevalence of HBoV in respiratory samples in the MENA.

Figure 3. The prevalence of HBoV in respiratory samples in the MENA.

View Image - Figure 4. The prevalence of HBoV in gastrointestinal samples in the MENA.

Figure 4. The prevalence of HBoV in gastrointestinal samples in the MENA.

The prevalence of HBoV in 14 countries of the MENA region.

Country First Author, Year Study Period Age Group HBoV Positive Sample Size Prevalence Type of Specimen HBoV Genotypes Study Design
Egypt Zaghloul (2011) [12] 2009–2010(8 months) Children(<5 years) 22 100 22.0% NPAs ND Case-control
18 100 18.0% Serum
Tabl et al. (2012) [13] 2010–2011(10 months) Children (<12 years) 20 200 10.0% NPAs ND Cross section
EL-Mosallamy et al. (2015) [14] 2013–2015(18 months) Children(<2 years) 2 100 2.0% Stool ND Cross section
Abdel-Moneim et al. (2016) [15] 2011–2015 Aged between 30 and 75 years 24 101 23.8% Colorectal cancer biopsy Genotype 1 Cross section
Abdel-Moneim et al. (2016) [16] 2013–2014(2 months) Children (<3years) 54 95 56.8% NP Genotype 1 Cross section
Meligy et al. (2016) [17] 2013–2014(5 months) Children (<3years) 8 51 18.2% NP and NPA ND Cross section
Amr et al. (2017) [18] 2015–2016(11 months) Children(<5 years) 19 123 15.4% NPAs ND Cross section
16 123 13.0% Serum
Hatem et al. (2019) [19] 2010–2014(48 months) All age groups with viral infection 1075 11 1.0% NP and OP ND Cross section
Abozahra et al. (2020) [20] 2018–2019(5 months) Children(<5 years) 7 75 9.3% NP Genotype 1 Cross section
5 75 6.7% Serum
Roshdy et al. (2020) [21] 2013–2014(11 months) All age groups 2 200 1.0% NPAs ND Cross section
Iran Naghipour et al. (2007) [22] 2003–2004(4 months) Children (<5 years) 21 261 8% NPAs or NP Genotype 1 Cross section
Nadji et al. (2010) [23] 2007–2008(11 months) Children(<17 years) 9 133 6.8% NPAs Genotype 1 Cross section
2006–2008(32 months) 6 47 12.8% Stool
Monavari et al. (2013) [24] 2010–2011(12 months) Children(<5 years) 16 200 8.0% Stool ND Cross section
Romani et al. (2013) [25] 2008–2010(24 month) All age groups 27 294 9.18% Stool Genotype 1, 2 and 3 Cross section
Shokrollahi et al. (2014) [26] 2009–2011(24 months) Children(<9 years) 6 80 8.0% Stool ND Cross section
Mortazavi et al. (2015) [27] 2014(5 months) Age group between 29 and 91 years 6 91 6.6% Throat swabs ND Cross section
Tabasi et al. (2016) [28] 2012–2013(6 months) Children(<2 years) 15 140 10.7% Throat swabs Genotype 1 Cross section
Moradi et al. (2017) [29] 2015–2016(10 months) Age group between 56 and 80 years 0 30 0.0% BAL and NP ND Cross section
Malekshahi et al. (2017) [30] 2013–2014(8 months) Children(<5 years) 0 71 0.0% Throat swabs and nasal washes ND Cross section
Niya et al. (2018) [31] 2011–2016 All age groups 1 66 1.5% Colorectal cancer biopsy Genotype 1 Case -control
Mohammadi et al. (2019) [32] 2016–2017(12 months) Children(<3 years) 10 75 13.3% NP Genotype 1 Cross section
Mohammadi et al. (2020) [33] 2017–2018(12 months) Children(<3 years) 67 500 13.4% NP ND Cross section
72 500 14.4% Stool
Hashemi et al. (2021) [34] NA Confirmed COVID-19 cases from all age groups 10 105 9.7% Throat swabs and NP ND Cross section
Iraq Atyah et al. (2017) [35] 2015–2016(8 months) Children(<15 years) 48 195 24.6% NP ND Cross section
Al-Mayah et al. (2018) [36] 2017–2018(2 months) Children(<5 years) 8 122 6.6% NP Genotype 1 Cross section
Shamiran et al. (2019) [37] 2017(3 months) Children(<5 years) 18 50 36.0% NP and blood ND Cross section
Hasan et al. (2020) [38] 2017–2018(2 months) Children(<5 years) 8 122 6.6% NP Genotype 1 Cross section
Yaseen et al. (2020) [39] 2018–2019(7 months) Children (<10 years) 31 80 38.8% Pharynx swab ND Cross section
28 80 35.0% Serum
Israel Hindiyeh et al. (2008) [40] 2006(11 months) Children (<10 years) 26 231 11.3% Nasal suction, NP, BAL, throat swab, sputum, pleural fluid ND Cross section
Jordan Kaplan et al. (2006) [41] 2003–2004(5 months) Children (<5 years) 57 312 18.3% NPA Genotype 1 Cross section
AL-Rousan et al. (2011) [42] 2007(11 months) Children (<13 years) 20 220 9.1% NPA Genotype 1 Cross section
Awad et al. (2020) [43] 2016(3 months) Children (<5 years) 12 479 2.5% NP ND Cross section
Kuwait Essa et al. (2015) [44] 2010–2013(31 months) All age groups 14 735 4.9% BAL, TA, NPAs and NP ND Cross section
Madi and A. AL-Adwani (2020) [45] 2018–2020(24 months) All age groups 111 5941 1.9% NPAs and throat swabs Genotype 1 Cross section
Mohammad et al. (2020) [46] 2017(11 months) Children (<10 years) 2 84 2.3% Stool Genotype 1 Cross section
Lebanon Finianos et al. (2016) [47] 2013–2014(11 months) Children (<16 years) 36 236 15.0% NPAs ND Cross section
Oman Khamis et al. (2012) [48] 2007–2008(12 months) Children (<5 years) 8 259 3.0% NPAs ND Cross section
Qatar Janahi et al. (2017) [49] 2010–2011(24 months) Children (<2 years) 15 369 4.1% NP ND Cross section
Al-Romaihi et al. (2019) [50] 2012–2017(71 months) Adult(>15 years) 286 37929 0.7% OP, NP and NPAs ND Cross section
Al-Romaihi et al. (2020) [51] 2012–2017(71 months) Children (<15 years) 1920 30946 6.2% Throat swabs, NP and NPAs ND Cross section
Nadeem et al. (2020) [52] 2013–2016 All age groups with respiratory illness 874 43106 2.0% OP and NP ND Cross section
Saudi Arabia Memish et al. (2012) [53] 2009(6 days) HCP age between31 and 49 years 0 184 0.0% Throat swabs and NP ND Cross section
Abdel-Moneim et al. (2013) [54] 2012(4 months) Children (<10 years) 18 80 22.5% NP Genotype 1 Cross section
Al-Ayed et al. (2014) [55] 2012–2013(9 months) Children (<5 years) 1 135 0.74% NP ND Cross section
Bubshait et al. (2015) [56] 2010–2011(12 months) Children with viremia (<5 years) 5 47 10.6% Serum ND Cross section
Memish et al (2015) [57] 2013(22 day) Pilgrims came from worldwide to do hajj or Umrah(>18 years) 2 1676 0.1% Nasal swabs ND Cohort
Eifan et al (2017) [58] 2014–2015(11 months) Children(<5 years) 171 2266 7.5% NP, NPAs and BAL ND Cohort
Abdel-Moneim et al. (2018) [59] 2016(11 months) Blood donors (adult) (20–48 years) 21 300 7.0% Whole blood sample Genotype 1 Cross section
Koul et al. (2018) [60] 2014–2015(6 MONTHS) Pilgrims returning from Saudi Arabia, adults between 26 and 60 years 2 300 0.7% Throat swabs and NP ND Cross section
Sudan Adam et al. (2018) [61] 2014(8 months) Children(<5 years) 5 437 1.1% Stool Genotype 1 Cross section
Tunisia Kapoor et al. (2010) [62] NA Children(<15 years) 32 96 33% Stool Genotype 1, 2,3 and 4 Case- control
Khalifa et al. (2019) [63] 2013–2014(15 months) Children(<1 years) 37 515 7.2% NPAs ND Cross section
Turkey Midilli et al. (2010) [64] NA All age groups 7 155 4.5% NPAs and throat swab Genotype 1 Cross section
Azkur et al. (2014) [65] 2011–2012(6 months) Children(<2 years) 3 55 5.4% NP ND Cross section
UYAR et al. (2014) [66] 2010(6 months) Children(<2 years) 3 62 4.8% NPAs ND Case-control
Akturk et al. (2015) [67] 2013–2014(7months) Children(<7 years) 30 1143 2.6% NP ND Cross section
ÇİÇEK et al. (2015) [68] 2002–2014(151 months) All age groups 18 5102 4% NP, BAL and NPAs ND Cross section
Demirci et al. (2016) [69] 2009(3 months) Children(<5 years) 8 120 6.7% NP ND Cross section
Erdem et al. (2016) [70] 2013–2014(26 months) Pilgrims (adult) (>15 years) 1 97 1% NP ND Cross section
Goktas et al. (2016) [71] 2014–2015(11 months) All age groups 91 845 10.76% NP ND Cross section
Bakir et al. (2020) [72] 2015–2017(32 months) Children(<18 years) 105 2310 4.5% NP ND Cross section
United Arab Emirates Alsuwaidi et al. (2018) [73] 2016-2017(3 months) Children(3-6 years) 0 18 0.0% NP ND A pilot study
Jeon et al. (2019) [74] 2015–2018(27 months) Children(<15 years) 0 198 0.0% Sputum, NP and BAL ND Cross section
Adults aged between15 and 64 years 2 718 0.3% Sputum, NP and BAL
Elderly(≥65 years) 0 446 0.0% Sputum, NP and BAL

NA: Not available, ND: Not detected, NPAs: Nasopharyngeal aspirates, NP: Nasopharyngeal swabs, OP: Oropharyngeal Swab, BAL: Broncho Alveolar Lavage, TA: tracheal aspirate, HCP: Health Care Provider.

HBoV and other viruses detected in patients with viral co-infection.

Country First Author, Year Viral Coinfection Rate Coinfected Viruses
Egypt Tabl et al. (2012) [13] 66.7% Respiratory syncytial virus
13.3% Para influenza
6.7% Influenza-B viruses
6.7% Influenza-A viruses
6.7% Adenovirus.
Iran Naghipour et al. (2007) [22] 14.0% Adenovirus
15% Respiratory syncytial virus
4.0% Influenza A virus
Tabasi et al. (2016) [28] 13.3% Respiratory syncytial virus
Mohammadi et al. (2019) [32] 40% Respiratory syncytial virus
Mohammadi et al. (2020) [33] 65.6% Respiratory syncytial virus
62.5% Rotavirus
Hashemi et al. (2021) [34] 100.0% Severe acute respiratory syndrome coronavirus 2
Iraq Atyah et al. (2017) [35] 4.6% Respiratory syncytial virus
3.6% Human metapneumovirus
Israel Hindiyeh et al (2008) [40] 69.2% Adenovirus
7.1% Respiratory syncytial virus
10% Parainfluenza virus 3
Jordan Kaplan et al. (2006) [41] 72% Respiratory syncytial virus
AL-Rousan et al. (2011) [42] 20% Respiratory syncytial virus
Kuwait Madi and A. AL-Adwani (2020) [45] 10.8% Respiratory syncytial virus
9.9% Human rhinoviruses
6.3% Influenza A virus
3.6% Adenovirus
Mohammad et al. (2020) [46] 50% Adenovirus
Lebanon Finianos et al. (2016) [47] 47.2% Adenovirus
36.1% Human rhinoviruses
Oman Khamis et al. (2012) [48] 62.5% Respiratory syncytial virus
Qatar Janahi et al. (2017) [49] 51.2% Respiratory syncytial virus
25.5% Rhinovirus
Turkey Azkur et al. (2014) [65] 33.3% Respiratory syncytial virus
33.3% Rhinovirus
33.3% Influenza A virus

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