Background
Rotavirus remains the most common cause of severe childhood diarrhea worldwide and of diarrheal mortality in developing countries [
1]. The main symptoms of rotavirus gastroenteritis (RVGE) are fever, abdominal pain, lethargy, diarrhea and vomiting that may lead to hypovolemic shock and dehydration [
2,
3]. Severe cases may lead to death [
4]. The World Health Organization (WHO) estimates that 527,000 children under the age of five years die of rotavirus disease each year [
5]. Children in the poorest countries account for 82% of rotavirus deaths [
6].
Rotavirus is transmitted by the fecal-oral route [
2]. Infection rates for rotavirus are highest in children under five years of age, with 95% of children between the age of three and five years affected [
7]. There is seasonality to rotavirus infection, with the majority of cases in temperate climates occurring in the winter months between November and February [
2,
8]. Seasonality in tropical and developing countries is less marked [
7].
Three of the seven sero-groups of rotavirus identified affect humans, known as groups A-C. The most dominant, group A, causes diarrheal diseases worldwide [
2]. Group A rotaviruses are classified into G and P-types, which are determined by the two outer layer viral proteins, VP7 and VP4, respectively. These two proteins elicit neutralizing antibody responses and therefore, protection from infection and disease is believed to be type-specific [
9]. Rotaviruses are ubiquitous in the animal kingdom, and therefore, interspecies transmission and more importantly, exchange of genetic material between animal and human strains through re-assortment can lead to the emergence of novel rotavirus strains of epidemiological significance [
9].
The incidence of infection with particular group A rotavirus serotypes and genotypes varies between geographical areas during a rotavirus season, and from one season to the next [
10]. Globally, viruses carrying either G1, G2, G3, G4, G9 and P[4] or P[8] are the most common causes of rotavirus disease in humans. G12 is also recognized as an emergent serotype, that may become important in human disease [
11].
Often, children suffering from RVGE require outpatient medical care, but in the presence of dehydration, admission to emergency or hospitalization and intravenous rehydration are necessary. Each year worldwide, rotavirus causes approximately 111 million episodes of gastroenteritis requiring only home care, 25 million office visits, and 2 million hospitalizations [
6]. By the age of five years, nearly every child will have an episode of RVGE, one in five will visit a clinic, and one in 65 will be hospitalized [
6]. Thus, RVGE imposes a heavy burden, not only by incurring direct medical costs, but also indirect costs due to productivity loss and other expenses [
3,
12,
13]. Currently available rotavirus vaccines protected against severe RVGE and were well tolerated; the implementation of immunization programs would be expected to reduce disease burden [
3].
Burden of illness data specific to the Middle East and North Africa is limited. The purpose of this study was to conduct a comprehensive literature review on the burden of rotavirus acute gastroenteritis on the pediatric population in these regions.
Methods
Literature search strategy
To identify and retrieve articles pertaining to the impact of rotavirus infection on the pediatric population (≤5 years, unless otherwise specified) in the Middle East and North Africa, a comprehensive literature search was conducted in the National Library of Medicine's Pubmed, the Center for Disease Control (CDC) rotavirus global surveillance (
http://www.cdc.gov/rotavirus/global_surveillance/surveillance.htm), and the WHO (
http://www.who.int/nuvi/rotavirus/en/). The search, limited to articles published from 1999 to 2009, covered the Middle East (Bahrain, Iran, Iraq, Israel Jordan, Kuwait, Oman, Qatar, Saudi Arabia, Syria, UAE, Yemen), North Africa (Algeria, Egypt, Libya, Morocco, Tunisia), as well as Turkey for its regional proximity. Search terms included: rotavirus, outcome*, mortality, death, incidence, prevalence, serotype, strain, cost*, economic*, burden, and resource use. Reviews and case studies were excluded.
Data extraction and analysis
For all studies, dates reported for data presented refer to the date when studies were conducted, which was often several years before the publication date.
In the case where several surveillance studies are published for a single country, a pooled average of the proportion of RVGE among cases of acute gastroenteritis was calculated and reported. Ranges across studies were also reported for each country. Where available, data on infection seasonality was collected and reported, in addition to variation over time in the proportion of RVGE.
Data was extracted for each serotype. Figures for distribution of rotavirus genotype combinations were taken from the most recent available data, except for Turkey. For this country, data from a prospective survey from 2004-2005 [
14] was used to replace a more recent publication (2005-2006 Ceyhan study [
15]), due to discrepancies in the serotype data reporting (combined serotyped data in the Ceyhan study [
15] adds up to 113%). Where two studies from the same year and the same country showed a similar serotype distribution, a weighted average across the studies was calculated to present as one figure. All other figures were reported as originally described in the source documents.
Mortality data included annual fatalities and mortality rates per 100,000 population under five years of age. For health outcomes of rotavirus acute gastroenteritis, data was extracted on disease severity as measured by the 20-point Vesikari scoring system [
16], and the severity and proportion of patients suffering from dehydration due to rotavirus acute gastroenteritis. The Vesikari scale is a numerical system used to assess RVGE disease severity, based on the duration and intensity of diarrhea and vomiting, intensity of fever and dehydration, and the need for treatment and hospitalization [
16]. A Vesikari score ≥11 is indicative of severe disease.
For healthcare resource use data, the following parameters were extracted for comparison across countries: hospital admission rates, need for intravenous rehydration, and duration of hospital stay. Cost-of-illness data included direct medical costs, out-of-pocket expenditures, and indirect costs attributed to lost productivity by parents of children suffering from RVGE. Costs are reported in 2008 US dollars.
No statistical analyses were performed for this review.
Discussion
Based on data collected from 44 studies in the Middle East and North Africa, this analysis shows that rotavirus imposes a heavy burden among children less than five years of age. Overall, the annual proportion of RVGE among reported episodes of pediatric gastroenteritis in the Middle East and North Africa region was 42% [
18]. This figure is similar to a published estimate of the proportion of RVGE (43%) from a prospective multicountry study in Western Europe [
58], further emphasizing the ubiquitous nature of the disease [
7]. However, when Middle Eastern and North African countries were compared to each other, large variations in proportion of RVGE estimates were observed, with a low of 16%-23% reported in Saudi Arabia, Tunisia, and Egypt, and a high of 44%-61% in Syria, Oman, and Kuwait. These variations may reflect actual differences in RVGE proportion but may also be related to variations in study design, which limit comparability across countries.
A considerable amount of information on serotype distribution in the countries of interest was retrieved, highlighting the predominance of G1P[8] and G2P[4]. These genotype combinations are also predominant in Western Europe [
59]. In the present study, the proportion of non-typable and partially typable genotype combinations varied widely across countries [
22,
26,
36,
37]. The reason for this discrepancy is not clear, although it might be due to differences in study design and setting, or to laboratory practice differences from country to country.
Several studies assessed the evolution of serotype distribution over time and the emergence of new rotavirus strains in the Middle East and North Africa. All of these prevalent (G2P[4] [
36,
38], G4P[8] [
18,
22,
26], G3P[8] [
44]) and emerging (G9P[8] [
17,
18,
21,
41]; G1P[4] [
46]) serotypes belong to the most commonly described strains of rotavirus that are responsible for gastroenteritis disease in humans [
10]. Interestingly, G12, a recently emerging serotype detected in Europe, Asia, and the Americas [
11,
60,
61], has not been reported in any of the studies captured in this review.
A wide inter-country variation was noticed in mortality rates due to RVGE, with the highest rates reported in Iraq and Yemen compared to less than one fatality in Bahrain, Israel, and Kuwait (Figure
6). Based on demographic indicators from UNICEF, the average annual mortality rate in the region was estimated at 39 per 100,000. This rate is considerably higher than in Europe, where rotavirus rarely results in child death (mortality rate below 10 per 100,000) [
55]. These inter-country and inter-region variations are in agreement with previous reports showing that children in the poorest countries account for 82% of rotavirus deaths [
6]. Because of data limitations, it cannot be concluded from this study whether differences in mortality rates are due to variations in clinical management of the disease.
The hospital admission rates and the use of intravenous rehydration were similar to European figures reported in the multicentre RVGE Epidemiology and Viral types in Europe Accounting for Losses in public health and society (REVEAL) study [
62]. As well, the higher rates of hospitalization and higher disease severity for rotavirus versus non-rotavirus acute gastroenteritis reported in this review were in line with data reported in Western Europe [
63].
Rotavirus cost information was very limited in the Middle East and North Africa. Per episode of RVGE, direct medical costs in the Middle East and North Africa ($467 to $1,117) were lower than those reported in Western Europe (ranging from 2008 US $1,949 in the UK to $2,398 in Sweden) [
62].
Study limitations are worth mentioning. Most published articles retrieved in this study reported serotype and epidemiological data; information on the burden of RVGE in terms of mortality, morbidity, and economic burden was limited. This in term restricted the evaluation of the global burden for the region. Most recent available data was considered to describe and compare serotype distribution across countries; however, the only available data was not necessarily recent and did not correspond to the same time frame in all countries. For example, the only serotype information for Libya was published in 2000 [
32], therefore conclusions on serotype distribution for this country may have changed, and comparison with 2008 data from other countries would be limited. Moreover, due to data limitations, a clear relationship between certain rotavirus genotypes and disease severity could not be established. Finally, variations in study setting and design may affect comparability of data.
Competing interests
HK, IO, and MMG declare that they have no competing interests. AEK is an employee of Merck Sharp & Dohme Corp. and potentially owns stock and/or holds stock options in the Company. YD is a fellow at Lehigh University; her fellowship was funded by Merck & Co.
Authors' contributions
HK & IO developed the search algorithm and drafted the manuscript. AEK, YD, and MMG participated in the design of the methodology and drafting of the manuscript. All authors read and approved the final manuscript.