Burden of Adenovirus, Astrovirus, Norovirus and Rotavirus Gastroenteritis in Egyptian Children during 2000-2017

Enteric viruses are the leading cause of severe dehydrating diarrhea among children, worldwide. The aim of this review was to estimate the burden of adenovirus (AdV), astrovirus (AstV), norovirus (NoV) and group A rotavirus (RVA) gastroenteritis in Egypt. Literatures published in PubMed and other sources (Science direct, google scholar) on the epidemiology and burden of AdV, AstV, NoV and RV among Egyptian children between 2000-2017 were collected. Data from each study was extracted and compared. The search identified 19 studies. AdV, AstV, NoV and RVA gastroenteritis were identified in 2-20%, 0-31%, 2.2-30% and 10.7-76.9%, respectively, with average of 3.6%, 7.2%, 10.5% and 32.5% of all cases of acute gastroenteritis. These viruses were occurred year-around with high detection rates in male and children younger than 12 months. The most common genotypes were HAstV-1 for astrovirus, G1P[8] for rotavirus, GGII.4 for norovirus. Children with AdV, AstV, RVA and NoV-positive acute gastroenteritis were more likely to have vomiting, diarrhea, abdominal pain, fever, various degrees of dehydration ranged from mild to severe dehydration. This systematic review documents that enteric viruses, particularly RVA, are significant pathogens of children diarrhea in Egypt. A vaccine covering multiple genotypes may reduce the morbidity and cost burden of AdV, AstV, RVA and NoV gastroenteritis in Egypt. Burden of Adenovirus, Astrovirus, Norovirus and Rotavirus Gastroenteritis in Egyptian Children during 2000-2017


Introduction
Acute diarrheal diseases are a major problem for public health, causing approximately 0.8 million deaths per year affecting mostly children ˂ 5 years old [1]. Although the deaths occur mostly in developing countries, diarrheal illness is the main cause of morbidity and mortality in children worldwide [2,3]. Enteric viruses are identified as the most significant causative agent of acute gastroenteritis (AGE) in children, accounting for about 70% of episodes [4]. Four virus families are often associated with AGE in children: adenoviruses (AdV), rotaviruses group A (RVA) and astroviruses (AstV) and noroviruses (NoV) [5].
Rotaviruses, belonging to the Reoviridae family, are classified into 50-P and 35 G-genotypes based on the differences in the nucleotide sequence of VP4 and VP7 genes [6]. RVA with combination of G and P genotypes have been stated in several epidemiological studies [7,8]. The most common five genotype combinations are G1P, G2P, G3P, G4P and G9P, causing about 75% of RVA infections globally [4,[8][9][10]. RVA infections are estimated to cause approximately 453,000 deaths among children below five years of age per year, mostly in developing countries [11].
Noroviruses (NoVs) are identified as the most common cause of AGE in humans, globally [12]. NoVs, within the Caliciviridae family, are small (27-40 nm in diameter) non-enveloped viruses containing a single-stranded RNA genome with a size of approximately 6.5-7.5 kb. NoV can be classified into 6 genogroups GI-GVI [13]. The three genogroups GI, GII and GIV have been recognized to infect human and they are subdivided into approximately 33 genotypes (9 GI, 22 GII and 2 GIV) [14]. The genotype GII. 4 are associated with worldwide outbreaks [14].
Human astroviruses, belonging to Astroviridae family, are nonenveloped viruses with a single-stranded RNA genome. HAstV have also been identified as a major cause of viral AGE in immunocompromised, children and the elderly subjects. HAstV are subdivided into eight serotypes and HAstV-1 is the most prevalent serotype with high seroprevalence rate ( ̴ 90%) in children younger than 5 years [17][18][19][20][21][22][23]. Routine diagnostic techniques for viral diarrhea are often based on the detection of most common enteric viruses (AdV, AstV, NoV and RVA) by immunoassays or by molecular methods.

Materials and Methods
Nineteen articles from Egypt were published between January 2000 and December 2017, have been collected from google scholar, science direct and PubMed websites with the keywords "enteric viruses, adenovirus, astrovirus, norovirus and rotavirus gastroenteritis". All articles published on these websites were collected without specific criteria. Detection of enteric viruses were conducted using a sensitive technique such as an enzyme immunoassay (EIA), polymerase chain reaction (PCR) and reverse-transcriptase polymerase chain reaction (RT-PCR). The prevalence, seasonal variation, gender distribution, age distribution, genotyping of enteric viruses and clinical features were extracted from all collected studies and compared.
The prevalence of enteric viruses as well as RVA genotypes were analyzed by two ways: a. Overall the period of sample collections b. During different periods according to the years of sample collections.

Distribution of norovirus genotypes in children with diarrhea
Two studies from Egypt contained data on norovirus genotypes. GGII was the most commonly detected genotype; it was identified in 71% of the cases, where GGII.4 was the predominated strain, it was identified in 45% of the cases, followed by GGIIb (     (13%). In the same study, GGI was detected in 29% of all positive samples where GGI.1 and GGI.9 were detected in 9.7% of all positive specimens while GGI.3, GGI.4, GGI.5 and GGI.15 were detected in 3.2% of all positive samples [24]. In the second study, GGI was detected in five of 220 (2.2%) diarrheal samples while GGII was not detected [26].

Clinical features, disease severity and Intravenous rehydration
Eight studies from Egypt provided us data on clinical features of gastroenteritis caused by enteric viruses [31][32][33]35,36,38,39,41]. The common clinical features resulted from the infections by these viruses were vomiting, diarrhea, abdominal pain, fever, various degrees of dehydration ranged from mild to severe dehydration. Children who received oral solution, oral solution packets to take at home and medication due to RVA infections was reported in one study by El-Shabrawi et al. (2015) [36]. In the same study, convulsions and bloody diarrhea was found in 5% and 20% of children infected with RVA, respectively [36]. The median durations of diarrhea due to RVA infection were 3.7 and 3 ± 2 days [36,39]. On the other hand, two studies reported that 94.4% and 18% of dehydrated children due to RVA gastroenteritis were received Intravenous fluid therapy [36,39]. No deaths were occurred among infected children with viral diarrhea in the all included studies.

Discussion
Acute Diarrhea is one of the major cause of deaths in infant and young children worldwide, particularly in developing countries [43]. To increase our knowledge about the impact of viral intestinal infections on children, a comprehensive survey on various enteric viruses was carried out in Egypt. This study included commercial EIA, PCR and RT-PCR to detect the most common enteric viruses associated with diarrhea. Our survey demonstrated that RVA is the main enteric virus associated with diarrhea in children, followed by norovirus, astrovirus and adenovirus. The frequency distribution in this survey agrees with results reported from study conducted in Saudi Arabia [44]. As reported by other investigators RVA was recorded as the principal cause for children diarrhea [45][46][47][48][49]. Furthermore, this survey supports the notion that NoV is the second most viral pathogen of diarrhea in children seeking medical attention [50,51]. Also, this survey supports other study that AstV, AdV are rarely implicated in children gastroenteritis [52].
Although the collected articles in this survey were published between 2000-2018, the sample collections were started from 1995 for astrovirus detection [38]. When we classified this survey into different periods according to the years of sample collections, we found that the higher prevalence of AdV was 12.8% during the recent years (2015-2017) of sample collection while the higher prevalence of AstV, NoV, In this survey, RVA typing showed that G1-G4, G9 and G10 are the circulated rotavirus strains in Egypt where G1 represents the most prevalent strain among children diarrhea. Furthermore, RVA G1P [8] was the most circulating genotype in children with acute diarrhea. This result agrees with studies from Egypt and other countries [25,39,40,[53][54][55]. G2P [4] was the most second circulating genotypes after G1P [8] and this finding agree with other studies from Vietnam and sub-Saharan Africa [54,55]. Khoury et al. reported that G1P [8] and GP [4] were the most circulated genotype combination in the Middle Eastern and North African, based on data collected from 1999 and 2009 [54]. These findings highlight the socioeconomic impact of the current vaccine in prevention of rotavirus diarrhea and confirm that RotaTeq vaccine (Whitehouse Station, NJ, USA), containing a mixture of 5 human serotypes G1-G4 plus P [8] and Rotarix vaccine (GlaxoSmithKline, Rixensart, Belgium), containing G1P [8], appear to be effective in reducing RVA diarrhea in Egypt. However, updating vaccine formulation are needed to contain other circulating serotypes such as G9 and G10 and the other predominant genotypes of RVA such as G2P [4] in Egypt.
NoV typing showed that NoV GGII.4 was the most detected genotype in Egyptian children diarrhea [24]. This observation agrees with previous studies from Tunisia, Australia and Japan [56][57][58][59]. However, this disagrees with a previous study from Egypt identifying GGI strains as the most circulated strains in children diarrhea [26]. Also, our analysis revealed that HAstV-I was the most prevalent genotype among Egyptian children with diarrhea and this finding agree with previous studies from Australia, Brazil and Hungary [60][61][62]. The variation in the detection rates of enteric viruses in the included studies can be explained by the variance in the conditions of these studies, such as the difference in the location of sample collection, number of tested samples, season of sample collection, concentration of viral antigens in the collected samples and the sampling methods.
The higher rates of AdV, AstV, NoV and RV antigens in the present survey were found in children ≤ 12 years of age. This observation may be resulted from the protection which acquired by maternal antibodies during the first year of child life then by the immunity which given after two years of life due to repeated infections [63]. Based on this finding, preventive strategies should be carried out during infancy. Furthermore, most of the included studies in this survey reported that males were more sensitive than females for infection with enteric viruses. Similar results were reported in studies from Jordan, Tunisia, Indonesia and Gabon [64][65][66][67]. In the current survey, enteric viral infections were found thought the year including cold, warm, spring seasons and this was reported in other studies [50,52,56,60,62]. The main symptoms of AdV, AstV, NoV and RVA gastroenteritis were vomiting, diarrhea, abdominal pain, fever and dehydration. These symptoms were reported in several reports conducted in Venezuela, Indonesia, Japan and France [51,66,68,69]. Study limitations are worth mentioning. The included articles in this survey are contained little data on AstV and NoV genotyping whereas no data was available on AdV genotyping. Moreover, no data was available on the burden of these viruses in terms of diarrhea duration, mortality, economic burden and healthcare resource utilization [24,[26][27][28].

Conclusion
Enteric viruses, especially RVA, gastroenteritis is a common illness associated with significant morbidity in Egyptian children. The results of this study provide useful data to public health. Furthermore, this genetic diversity of AstV, NoV, RVA types in Egypt have been reported in this survey and based on these data updating vaccine formulation, covering the most common serotypes may help to decrease the burden of gastroenteritis resulted from the infections by these viruses in the Egypt. G9P [8] G9P [6] G9P [8] G4P [8] G3P [8] G3P [4] G2P [4] G2P [8] G1P [6] G1P [4] G1P [8] Figure 4: Distribution of RVA G-P combination genotypes among Egyptian children diarrhea during different periods.