Prevalence of Human Sapovirus in Low and Middle Income Countries

Background Sapovirus (SV) infection is a public health concern which plays an important role in the burden of diarrhoeal diseases, causing acute gastroenteritis in people of all ages in both outbreaks and sporadic cases worldwide. Objective/Study Design The purpose of this report is to summarise the available data on the detection of human SV in low and middle income countries. A systematic search on PubMed and ScienceDirect database for SV studies published between 2004 and 2017 in low and middle income countries was done. Studies of SV in stool and water samples were part of the inclusion criteria. Results From 19 low and middle income countries, 45 published studies were identified. The prevalence rate for SV was 6.5%. A significant difference (P=0) in SV prevalent rate was observed between low income and middle income countries. Thirty-three (78.6%) of the studies reported on children and 8 (19%) studies reported on all age groups with diarrhoea. The majority (66.7%) of studies reported on hospitalised patients with acute gastroenteritis. Sapovirus GI was shown as the dominant genogroup, followed by SV-GII. Conclusion The detection of human SV in low and middle income countries is evident; however the reports on its prevalence are limited. There is therefore a need for systematic surveillance of the circulation of SV, and their role in diarrhoeal disease and outbreaks, especially in low and middle income countries.


Introduction
An estimated number of 6.3 million deaths of children under the age of 5 years suffering from diarrhoea have been reported worldwide [1,2]. In Africa, death due to diarrhoeal disease remains a major health concern, though it has decreased from 2.6 million to 1.3 million between 1990 and 2013 [3]. Diarrhoeal disease is the important cause of morbidity and mortality in low and middle income countries, also the third most frequent cause of death and greatest contributor to the burden of disease in children younger than 5 years of age [4]. The infection of human intestinal tract occurs through transmission at the household level due to different pathways such as ingestion of contaminated food and water, poor waste disposal, and person-to-person interactions in the households and community [4,5]. Low and middle income countries still face challenges like inadequate human waste disposal, poor water quality, poor health status, and disease transmission through faecal-oral route [6].
This review summarises reports on SV detection and typing in low and middle income countries. In addition, it highlights the need to establish the relatedness of circulating SV strains in environmental (water) samples and clinical samples from communities in low and middle income countries (particularly rural settings). The time-frame chosen was 2004 to 2017 because of the availability of published data on human SV within the low and middle income countries.

Methodology
Two literature searches were carried out. The first literature search was performed using the terms: calicivirus, sapovirus, and developing countries, as listed by National Institutes of Health PUBMED library and ScienceDirect. A second literature search was independently done for each of the 139 "developing" countries accessed from the list published by the Society for the Study of Reproduction (http://www.ssr.org). Furthermore, the identified countries were then assessed according to the 2018 World Bank analytical classification report (http://datahelpdesk.worldbank.org/knowledgebase/articles/ 906519). For a successful search, each of the countries' names was combined with the following keywords: calicivirus, sapovirus, enteric viruses, and gastroenteritis. Studies identified by the search terms were selected for inclusion in the review based on the following inclusion criteria: (a) Studies limited to human SV detected in clinical specimen and environmental water samples, reported in the 21st century. (b) SV studies using laboratory molecular techniques including nested-PCR (nPCR), real time-PCR (RT-PCR), and RT-multiplex PCR.
Studies were excluded from the review if SV was detected in other mammalian species or animals or if the study was conducted in high income countries. In case of duplication of studies by authors, only one article was included. Data was extracted from each selected study when provided: country name and its economic status (i.e., low income, lower, and upper middle income) as per the analytical classification report by World Bank, study setting (hospitalised, outpatient, and environment), study population (age group), population size, duration of the study, diagnostic method used, number of samples tested for SV (including their genogroups and genotypes), first author, and year of publication (Tables 1, 2 and 3).
The difference of SV data in middle and low income countries was analysed for statistical significance by Student's t-test using the simple interactive statistical analysis (SISA) at http:home.clara.net/sisa. Result with P < 0.05 was considered significant.

Results
A total of 138 articles published from 2004 to 2017 were identified from 19 low and middle income countries. After  Shen et al [28] 4 Advances in Virology  [35] Advances in Virology 5

Genogroup not defined
Pongsuwanna et al [45] 6 Advances in Virology    The prevalence rate of SV from the 41 documented studies in low and middle countries was 6.19% with a range from 0.2% to 39%. Further breakdown showed significant difference (P =0) in SV prevalence rate between low income (10.40%) and middle income (5.86%) countries. Although data on the prevalence of SV in African countries is limited, thus far, eight studies have been conducted in urban settings. Detection of SV from children in Africa is recorded with different incidence rates: in Tunisia [0.8%] [ [3]. A predominance of SV-GIV (53/221, 24%) was noted in the South African study done on stool samples from hospitalised children with gastroenteritis [55].
Only 8.9% of studies reported SV in the environmental and waste water samples from low and middle income countries. The detection of SV-GI, SV-GII, and SV-GIV has been reported from polluted water sources by wastewaters and also on samples collected from treatment plants within selected areas of SA [58][59][60]. Sapovirus genogroups I and II were identified from river water samples, with detection rate of 48.5% (48/99) [58], while, in Brazil, SV-GI (genotypes 1 and 2) were detected (33%, 51/156) from the wastewaters [22], Table 3.

Discussion
This review provides a summary of studies conducted in developing countries on the detection of human SV. Only 45 (41 stool samples, 3 water samples, and 1 both stool and water sample) studies satisfied the inclusion criteria of this review highlighting the importance for systematic surveillance monitoring human SV circulating in developing countries (rural and urban communities). Very little is known about the contribution of human SV to diarrhoeal disease in developing countries; this is reflected in the fact that reported studies were only from 19 identified countries which include 5 African countries, namely, Burkina Faso, Ethiopia, Kenya, South Africa, and Tunisia (Table 2). A total of 78.6% (33/42) studies reported on children ≤5 years of age from the collected data, highlighting the role of SV in diarrhoeal disease amongst children in the developing countries. Hence, SV and other emerging enteric viruses, being underappreciated, can be an important cause of Norovirus negative outbreaks as reported by Lee and colleagues [61]. In addition, since it is difficult to culture human SV on cell lines [13], specialised molecular laboratories are needed for the investigation of such virus in the developing countries. Because of lack of funding and skills, the prevalence of enteric viruses is underreported in Africa and other developing countries [62] Most of the studies (66.7%; 28/42) were done in hospitalised patients, and this might be due to the fact that SV infection sometimes leads to hospitalisation as illustrated from other studies [49,63]. GEMS study reported SV amongst other enteric pathogens to have been associated with moderate to severe diarrhoea in developing countries [64]. The Millennium Development Goals (MDG) 2015 report shows disadvantaged settings being vulnerable as compared with the advantaged or developed settings, highlighting the effectiveness and affordability of treatments, and improved service delivery and political commitment playing a role in such settings. The statistical analysis of this review similarly Advances in Virology 9 showed a significant difference in the prevalence of SV in low income than in middle income countries (P=0).
The circulation of SV genogroups shows variability, with SV-GI and SV-GII detected frequently, while SV-GIV and SV-GV are rarely detected comparing to other genogroups [16]. An African study (Burkina Faso) reported SV-GII as the predominated strain, mostly in outpatients with diarrhoea (81.5%: 22/27), suggesting that this genogroup may be less virulent and require fewer hospital admissions. However, additional studies on outpatients will have to be conducted to confirm this observation. Although the detection of SV-GII is seen in diarrhoeal samples, it might be less virulent to cause severe symptoms leading to hospitalisation of patients, unlike SV-GI which is commonly known to be associated with severe symptoms and frequently detected in patients presenting with gastroenteritis [16,32]. The detection of SV (GI, GII, GIV, and GV) in gastroenteritis outbreak cases has been reported in high income countries, however with less detection rate of SV-GII in both cases [14,17,61,65].
Human SV infections cases relating to acute gastroenteritis in people of all ages have been identified worldwide [14]. Notwithstanding the potential selection biases present based on the studies available for inclusion, this review shows that the prevalence in children may be higher than in adults in low and middle income countries. In addition, the GEMS study in low and middle income countries highlights diarrheal disease in children as a leading cause of illness and death and also increasing the risk of delayed physical and intellectual development [66]. It has been reported that sporadic and outbreak cases caused by enteric viruses spread mainly by personto-person contact, contaminated surfaces or objects, and contaminated water or food [67]. Therefore children are more vulnerable than adults within such exposed environment, probably because of immune system development. However, previous studies noted that gastroenteritis symptoms are usually self-limiting, and patients usually recover within a couple of days depending on the individual immune's response [49,63]. Adults are likely to consider self-treatment by oral rehydration solution (ORS) which is the safe, effective, and low cost therapeutic option preventing dehydration [68], hence not consulting in healthcare facilities or likely due to self-respect.
Sapoviruses, like other enteric viruses, play an important role in the burden of disease worldwide. The GEMS conducted a three-year study in selected low and middle income countries, amongst children aged 0 to 59 months, and reported the detection of SV (3.5%) associated with diarrhoea [64]. However, there is no surveillance system on SV infection and prevalence in low and middle income countries, which means underreporting of sporadic cases of human SV and its epidemic are underestimated. Nevertheless, detection and comparison of the SV strains circulating in low and middle income countries (especially Africa) are currently underreported and this could be due to various techniques used for sampling and detection, including study site conditions.
Information on seasonality, patient history, area settings, and predicated pattern of transmission of viruses within the community provides knowledge needed to implement public health intervention strategies. Furthermore, detection of enteric viruses (such as SV) in environmental samples gives awareness of the circulation of infectious viral particles within the population and health-hazards which might be associated with the environment. The predictable effects of human waste disposal, water quality, and high rate of immunocompromised society have been a big concern in low and middle income countries, but there are still few documented reports on the detection of SV from environmental samples. This is highlighted by the finding of this study with high prevalence of SV in low income countries. The survival and development of children depend on good hygiene practices and use of clean drinking and domestic water on daily basis [4]. Monitoring of genetic diversity of the current circulating or emerging SV genogroups, possible water-borne transmission, and possible zoonotic infections amongst the communities is critical, and studies which can show the transmission of SV between the environment(s) (especially river water), domestic animals, and human should be considered, and the role that SV plays in diarrhoeal diseases [69].

Conclusion
This review found substantial evidence of SV proportion associated with diarrhoeal disease in low and middle income countries. However there is limited data reporting the detection of circulating SV strains. Therefore systematic surveillance of SV circulation within the communities in low and middle income countries is needed to assess sufficiently its role in diarrhoea disease.