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Hospital-based surveillance of rotavirus gastroenteritis among children under 5 years of age in the Republic of Ivory Coast: a cross-sectional study

Objectives To estimate the proportion of rotavirus gastroenteritis (RVGE) among children aged less than 5 years who had been diagnosed with acute gastroenteritis (AGE) and admitted to hospitals and emergency rooms (ERs). The seasonal distribution of RVGE and most prevalent rotavirus (RV) strains was also assessed. Design A cross-sectional hospital-based surveillance study. Setting 5 reference paediatric hospitals across Abidjan. Participants Children aged less than 5 years, who were hospitalised/visiting ERs for WHO-defined AGE, were enrolled. Written informed consent was obtained from parents/guardians before enrolment. Children who acquired nosocomial infection were excluded from the study. Primary and secondary outcome measures The proportion of RVGE among AGE hospitalisations and ER visits was expressed with 95% exact CI. Stool samples were collected from all enrolled children and were tested for the presence of RV using an enzyme immunoassay. RV-positive samples were serotyped using reverse transcriptase-PCR. Results Of 357 enrolled children (mean age 13.6±11.14 months), 332 were included in the final analyses; 56.3% (187/332) were hospitalised and 43.7% (145/332) were admitted to ERs. The proportion of RVGE hospitalisations and ER visits among all AGE cases was 30.1% (95% CI 23.6% to 37.3%) and 26.9% (95% CI 19.9% to 34.9%), respectively. Ninety-five children (28.6%) were RV positive; the highest number of RVGE cases was observed in children aged 6–11 months. The number of GE cases peaked in July and August 2008; the highest percentage of RV-positive cases was observed in January 2008. G1P[8] wild-type and G8P[6] were the most commonly detected strains. Conclusions RVGE causes substantial morbidity among children under 5 years of age and remains a health concern in the Republic of Ivory Coast, where implementation of prevention strategies such as vaccination might help to reduce disease burden.

• The main focus of this study was to estimate the proportion of RV among young children hospitalized for acute gastroenteritis (AGE) or treated at emergency rooms (ER) for AGE.
• Additionally, we sought to determine the seasonal distribution of RVGE and to identify the prevalent RV types in the study population.

Key messages
• RVGE accounts for about 28.6% of AGE hospitalizations and 30.1% ER visits in the Republic of Côte d'Ivoire and particularly affects children aged less than 24 months.
• The number of RVGE cases peaked during July and August 2008. The most prevalent RV strains were G1P [8] wild-type and G8P [6].
• Implementation of preventative measure such as RV vaccination could help to reduce the disease burden of RVGE in the Republic of Côte d'Ivoire. Strengths and limitations of this study: • The study was conducted in large pediatric hospitals across the city and hence our findings are likely to be representative of the whole population.
• The systematic approach followed to enroll children enabled easy identification of AGE cases.
• Only a reduced proportion of all the reported AGE cases could be enrolled in this study and included only severe cases.

INTRODUCTION
Wild-type, rotavirus (RV) causes approximately 111 million episodes of gastroenteritis (GE), 25 million clinic visits, two million hospitalizations and over 453,000 deaths per year among children younger than five years of age. [1,2] It has been reported that RV mortality is the highest among the low income countries in Asia, Africa and Latin America. [3] A systematic review and meta-analysis (2009) of published studies reported that, in sub-Saharan Africa, the overall mortality rate associated with RV infection in children under five years of age was 243.3 (95% CI 187.6-301.7) deaths per 100,000 children. [4] Globally, RV infection rates are highest among children aged less than five years, with approximately 95% children having experienced at least one episode of RVGE by the time they are five years of age. [5] RVGE is characterized by fever, diarrhea and vomiting that lead to severe dehydration and increased hospitalization. Over 90% of children with RVGE suffer from dehydration-associated mortality due to diarrhea and associated vomiting. [6][7][8] It has been suggested that RV infections are more common during the cooler months of the year and that RVGE disease burden is similar in both high and low income nations. [1] However, due to malnutrition and lack of access to appropriate treatment facilities, it is children in the low-income countries who die more frequently. [1] As improvements in hygiene and sanitation have not been associated with reduction in the incidence of RV-associated diseases, [9] vaccination against RV is therefore considered as a public health priority for low income nations. [10] The introduction of RV vaccination could have potential and visible benefits to children aged less than three years, and might assist the reduction of diarrhea-associated childhood morbidity and mortality in low income countries and of RV-associated hospitalizations in high income countries. [11,12] The most common RV serotypes associated with RVGE circulating worldwide are G1, G2, G3 and G4. [13] In addition to these, G9 has emerged as a globally important serotype in the last decade. [14] Together, these serotypes are responsible for 95% worldwide pediatric RVGE cases. [15] In the Republic of Côte d'Ivoire, the epidemiology of RV infection has been followed in several small studies conducted in Abidjan, [16][17][18][19][20][21] but recent data on RVGE disease burden for this region are limited. Data on RVGE disease, the number of hospitalizations and the number of emergency room (ER) visits following acute GE (AGE) are critical to formulate effective policies to control RV-related AGE. These data are also important to fully determine the need for RV vaccines and understand the possible impact of their introduction.
This study aimed to estimate the proportion of RVGE among children younger than five years of age who were diagnosed with AGE and admitted to hospitals and ERs. Seasonal distribution of RVGE and identification of prevalent RV types in the Republic of Côte d'Ivoire was also studied. were also recorded. The severity of RVGE was defined according to the Vesikari Scale (mild: score <7; moderate: score 7-10 and severe: score ≥11). [22] Stool samples collected within 4-10 days of the onset of GE were refrigerated (4°C-8°C), frozen (-20°C to -70°C) and then transported to Pasteur Institute, Abidjan, within 72 hours of sample collection. RV testing was performed using IDEIA rotavirus kit (DAKO Ltd., Cambridgeshire, UK) provided by the regional laboratory (West Africa Regional Rotavirus Reference laboratory). RV positive stool samples were subsequently tested using reverse transcriptase-polymerase chain reaction (RT-PCR) of the VP7 and VP4 genes followed by reverse hybridization at DDL Diagnostic Laboratory (Rijswijk, the Netherlands) to identify G and P genotypes and to differentiate the presence of wild-type G1 RV from the vaccine strain virus. [23] As a complementary tool, sequence analysis was performed to identify the most prevalent genotypes for samples that yielded an aberrant or unclear pattern. The resulting sequence was analyzed by BLAST search against the GenBank database to determine the RV genotype. [23] Analyses All children meeting the pre-defined eligibility criteria were included in the final analyses.
Age at onset, the seasonal distribution of RVGE and the occurrence of RV types were recorded. The occurrence of severe dehydrating RVGE (based on Vesikari scale, [22]) administered treatment (including intravenous [IV] re-hydration), duration of hospitalization and outcome were all reported.
All statistical analyses were performed using Statistical Analysis System (SAS®) version 9.2 and the graphs were generated using Microsoft Excel ® . Categorical data such as gender, seasonal distribution and disease severity were presented as proportions with one decimal. Burden of GE/ RVGE among hospitalizations/ ER visits were expressed as proportions with their 95% exact confidence interval (CI).
Exploratory analyses of estimation of the crude odds ratio were performed using univariate logistic regression considering RV status as the outcome variable with clinical characteristics and discharge outcome as confounding factors. Multinomial univariate logistic regression was also explored to estimate the association between outcome at discharge as the dependent variable and RV status and nutritional status as the independent factors. The 95% Walds CI was also estimated.

Demographic characteristics
A total of 1330 children (917 hospitalized and 413 visiting ERs) with AGE were identified from hospital logs, of whom 357 children were enrolled into the study.
Informed consent was not collected from the patents/ guardians of 973 children, due to parent refusal, samples not collected, and failure of the surveillance to capture the children. The mean age (standard deviation) of enrolled children was 13.6 months (± 11.14 months) ( Table 1).
The number of children hospitalized and those who visited the ER for GE stratified by age groups is shown in Table 2. Ninety-five children (28.6%) were RV positive, of which over 80% occurred in children aged less than 24 months ( Table 2). The highest number of RVGE cases was reported in children aged 6-11 months (40.0% [38/95]).
The percentage of children recording the symptoms associated with GE (diarrhea, vomiting and fever) was similar across RV positive and negative groups. However, a significant (P-value = 0.0037) association between vomiting and RV positive status was observed prior to hospitalization (Table 3). Nutritional status based on weight indicated that children who were adequately and moderately malnourished were similar across both RV positive and negative groups. However, a higher number of severely malnourished children were observed in the RV negative group (Table 3).
Oral rehydration was the most common treatment used for GE in both RV positive and negative groups.  In the present study, RV disease burden was predominantly observed among young children (aged 6-24 months), which is in line with previous studies conducted across the African continent. [9] A study conducted in Nigeria showed that over 90.0% of RVGE positive cases were observed in children aged less than two years [24] and two independent studies conducted in Egypt (1995)(1996) [25] and Libya (October 2007-September 2008) [26] indicated that the incidence of RVGE was highest among children aged 6-11 months; all comparable to the results of the present study.

Funding
GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took in charge all costs associated with the development and the publishing of the present manuscript.

Competing interests
All the authors have no competing interest to declare.

Trademark
DAKO RV EIA is a trademark of DAKO Ltd., Cambridgeshire, UK.

Study design 4
Present key elements of study design early in the  Coast is substantial and recent epidemiological data are limited.
• The main focus of this study was to estimate the proportion of RV among young children hospitalized or treated at emergency rooms (ER) for acute gastroenteritis (AGE).
• We also investigated the seasonal distribution of RVGE and the prevalent RV types in the study population.

Key messages
• RVGE accounts for about 28.6% of AGE hospitalizations and 30.1% ER visits in the Republic of Ivory Coast and particularly affects children younger than 24 months of age.
• The number of RVGE cases peaked during July and August 2008. The most prevalent RV strains were G1P [8] wild-type and G8P [6].
• Implementation of preventative measure such as RV vaccination could help to reduce the burden of RVGE in the Republic of Ivory Coast. Strengths and limitations of this study: • Our study was conducted in large city-based pediatric hospitals and our findings are therefore likely to be representative of the whole population.
• Our systematic approach for enrolment allowed the easy identification of AGE cases.
• Our study enrolled only a proportion of all reported AGE cases and only severe cases were included. RVGE is characterized by fever, diarrhea and vomiting, leading to severe dehydration and increased hospitalization. Over 90% of children with RVGE suffer from dehydration-associated mortality due to diarrhea and associated vomiting. [6][7][8] It has been suggested that RV infections are more common during the cooler months of the year and that RVGE disease burden is similar in both high and low income nations. [1] However, due to malnutrition and lack of access to appropriate treatment facilities, it is the children from the low-income countries who die more frequently. [1] As improvements in hygiene and sanitation have not been accompanied by reductions in the incidence of RV-associated diseases, [9] vaccination against RV is therefore considered as a public health priority for low income nations.
[10] The introduction of RV vaccination could have significant benefits for children aged less than three years, and might help to reduce diarrhea-associated childhood morbidity and mortality in low income countries and RV-related hospitalization in high income countries. [11,12] The most common globally circulating RV serotypes associated with RVGE are G1, G2, G3 and G4. [13] In addition, G9 has emerged over the past decade as a globally important serotype. [14] Together, these serotypes are responsible for 95% of worldwide pediatric RVGE cases. [15] The epidemiology of RV infection has been followed in several small studies conducted in Abidjan in the Republic of Ivory Coast, [16][17][18][19][20][21]

Demographic characteristics
A total of 1330 children (917 hospitalized and 413 visiting ER) presenting AGE were identified from hospital logs. Of these, 357 children were enrolled into the study. Informed consent was not collected for 973 children, due to: parent refusal; non-collection of samples; and failure of the surveillance to capture the cases. The mean age (standard deviation) of the enrolled children was 13.6 months (± 11.14 months) ( Table 1).

Proportion of GE and RVGE hospitalizations
The proportion of all AGE-related hospitalizations and ER visits that were The seasonal distribution of RV-attributable GE hospitalization is shown in Figure   2. The number of GE cases was highest in July and August 2008 and the percentage of RV positive cases was highest in January 2008.

Clinical characteristics of GE and RVGE hospitalizations
Among RV positive and negative children, severe GE (score ≥11 on the Vesikari scale) was recorded in 64.2% (61/95) and 55.5% (131/236) children before hospitalization, respectively (Table 2). The percentage of children recording GE-associated symptoms (diarrhea, vomiting and fever) was similar across RV positive and negative groups before hospitalization. However, a significant (P-value = 0.0037) association between vomiting and RV positive status was observed before hospital admission ( Table   2).
Nutritional status based on weight indicated that adequately and moderately malnourished children were distributed similarly across both RV positive and negative groups. However, a higher number of severely malnourished children was observed in the RV negative group (   Figure 3. In the present study, RV disease burden was predominantly observed among young children (over 90.0% [87/95] were aged up to 23 months), which is consistent with previous studies conducted across the African continent. [9] A study conducted in Nigeria showed that over 90.0% of RVGE positive cases were observed in children aged less than two years [24] and two independent studies conducted in Egypt (1995)(1996) [25] and Libya (October 2007-September 2008) [26] indicated that the incidence of RVGE was highest among children aged [6][7][8][9][10][11] months; all comparable to the results of the present study.
As observed in previous studies conducted in sub-Saharan Africa between 1975 and 1992, [9] most GE cases in this study were observed between July and August 2008. where malnourishment has been associated with a considerable risk of diarrheaassociated mortality. [27,28] The circulation of mixed RV types in the African countries has been previously reported. [29,30] In this study, although wild-type G1P [8]

Competing interests
All the authors have no competing interest to declare.

Trademark
DAKO RV EIA is a trademark of DAKO Ltd., Cambridgeshire, UK.

Figure 1: Distribution of GE cases by RV status by age groups (N = 332)
Note: RV status of one subject in the age group 0-5 Months was unknown

Trial registration: Not applicable
• We also investigated Additionally, we sought to determine the seasonal distribution of RVGE and to identify the prevalent RV types in the study population.

Key messages
• RVGE accounts for about 28.6% of AGE hospitalizations and 30.1% ER visits in the Republic of Côte d'IvoireIvory Coast and particularly affects children aged less younger than 24 months of age.
• The number of RVGE cases peaked during July and August 2008. The most prevalent RV strains were G1P [8] wild-type and G8P [6].
• The Our systematic approach for followed to enrollment children enabled allowed the easy identification of AGE cases.
• Only Our study enrolled only a reduced proportion of all the reported AGE cases could be enrolled in this study and included only severe cases were included.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  deaths per 100,000 children (95% CI 187.6-301.7). [4] Globally, RV infection rates are also highest among younger children aged less than five years, with approximately 95% children having experiencinged at least one episode of RVGE by the time they are reach five years of age. [5] RVGE is characterized by fever, diarrhea and vomiting, that leading to severe dehydration and increased hospitalization. Over 90% of children with RVGE suffer from dehydration-associated mortality due to diarrhea and associated vomiting. [6][7][8] It has been suggested that RV infections are more common during the cooler months of the year and that RVGE disease burden is similar in both high and low income nations. [1] However, due to malnutrition and lack of access to appropriate treatment facilities, it is the children in from the low-income countries who die more frequently. [1] 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  As improvements in hygiene and sanitation have not been associated withaccompanied by reductions in the incidence of RV-associated diseases, [9] vaccination against RV is therefore considered as a public health priority for low income nations. [10] The introduction of RV vaccination could have significant potential and visible benefits to for children aged less than three years, and might help to assist the reducetion of diarrhea-associated childhood morbidity and mortality in low income countries and of RV-associated related hospitalizations in high income countries. [11,12] The most common globally circulating RV serotypes associated with RVGE circulating worldwide are G1, G2, G3 and G4. [13] In addition to these, G9 has emerged over the past decade as a globally important serotype in the last decade. [14] Together, these serotypes are responsible for 95% of worldwide pediatric RVGE cases. [15] In the Republic of Côte d'Ivoire, tThe epidemiology of RV infection has been followed in several small studies conducted in Abidjan in the Republic of Ivory Coast, [16][17][18][19][20][21]
Most of the children hospitalized and visiting the ER due to AGE corresponded to children under two years of age (84.8% and 84.5%, respectively). The number of RV positive and negative children hospitalized and those who visited the ER for GE stratified by age groups is shown in Figure 1Table 2. Ninety-five children (28.6%) were RV positive, of which whom over 80% occurred were in children aged less than 24 months ( Table 2). The highest number of RVGE cases was reported seen in children aged 6-11 months (40.0% [38/95]) ( Figure 1). The seasonal distribution of RV-attributable GE hospitalizations attributed to RV infection is shown in Figure 21. The number of GE cases was highest in July and August 2008 and the percentage of RV positive cases was highest in January 2008.
The percentage of children recording the GE-associated symptoms associated with GE (diarrhea, vomiting and fever) was similar across RV positive and negative groups before hospitalization. However, a significant (P-value = 0.0037) association between vomiting and RV positive status was observed prior tobefore hospital admissionization (Table 23).
The results of this study need to be interpreted in the light of several strengths and limitations. Among the strengths, the systematic approach followed in this study to enroll identify children by checking the hospital and ER logbooks enabled easy identification of AGE cases using standard case definitions. Secondly, the study was conducted in reference reference hospitals that reported seeing over 1,300

CONCLUSION
RVGE in children aged less than five years continues to be a major public health challenge in the Republic of Côte d'IvoireIvory Coast. In our study, Tthe disease, which peakeds in July and August, mainly affecteds infants aged 6-11 months.

Contributors
AKC was the principal investigator and contributed to the conception, design, analysis and interpretation of the study. AKV and YAJ coordinated the study together with AKC and contributed to the interpretation of the results. All authors participated in the development of this manuscript.

Funding
GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took in charge all costs associated with the development and the publishing of the present manuscript.

Competing interests
All the authors have no competing interest to declare.