Original Article Prevalence of severe acute rotavirus gastroenteritis and intussusceptions in Ghanaian children under 5 years of age Christabel C. Enweronu-Laryea1, Kwamena W. C. Sagoe2, Hope Glover-Addy3, Richard H. Asmah4, Julius A. Mingle2, George E. Armah5 1 Department of Child Health, University of Ghana Medical School, Accra, Ghana 2 Department of Microbiology, University of Ghana Medical School, Accra, Ghana 3 Department of Surgery, Korle Bu Teaching Hospital, Accra, Ghana 4 School of Allied Health Sciences, University of Ghana, Legon, Ghana 5 Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana Abstract Introduction: Vaccination is the most effective preventive strategy against rotavirus disease. Regional differences in prevalent rotavirus genotypes may affect vaccine efficacy. Pre-vaccine surveillance for burden of rotavirus disease, prevalent rotavirus genotypes, and association between rotavirus disease and intussusceptions helps in monitoring the impact of vaccination. Methodology: A prospective study was conducted from January 2008 to December 2009 in children younger than five years hospitalized for longer than 24 hours with acute gastroenteritis. Data on confirmed cases of intussusception were collected retrospectively. Stools were tested by enzyme immunoassay, reverse-transcriptase polymerase chain reaction and nucleotide sequencing. Results: Acute gastroenteritis (AGE) caused 13.1% (2,147/16,348) of hospitalizations among children under five years. Stools were tested for 50.2% (1077/2147) of AGE cases. Of these, 49% (528/1077) were rotavirus positive. Rotavirus gastroenteritis, non-rotavirus gastroenteritis, and intussusceptions were most prevalent in children under 15 months [80.3%, 74% and 91% respectively]. Rotavirus was detected from more than 60% of acute gastroenteritis cases during peak months. The prevalence of intussusception showed no seasonal pattern. The peak ages of six to twelve months for acute gastroenteritis and five to eight months for intussusception overlapped. G1, G2 and mixed G/P genotypes were common in the isolated rotaviruses. Conclusion: Rotavirus gastroenteritis causes significant morbidity in children younger than five years of age in Ghana. Although the peak age of rotavirus gastroenteritis and intussusceptions overlapped, there was no seasonal correlation between them. The high prevalence of mixed G/P genotypes in Ghanaian children may affect the effectiveness of vaccination. Key words: rotavirus; gastroenteritis; intussusceptions; genotype; vaccination J Infect Dev Ctries 2012; 6(2):148-155. (Received 18 October 2010 – Accepted 14 June 2011) Copyright © 2012 Enweronu-Laryea et al. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Introduction and parasitic diarrheal diseases than hospitalization Rotavirus is the most common cause of acute from rotavirus disease [5,6]. Vaccination is gastroenteritis (AGE) in children younger than five considered the most effective public health strategy years of age worldwide. Each year two million to reduce rotavirus disease burden [7]. children younger than five years are hospitalized with Intussusception, a known cause of acute rotavirus AGE and an estimated 527,000 children die. intestinal obstruction in children younger than five5 The majority of these deaths occur in developing years of age, is potentially lethal. The etiology of countries [1,2]. Rotavirus causes about 30-50% of intussusception is poorly understood. There has been diarrheal diseases in young children and the no convincing evidence to date that it is caused by prevalence of severe rotavirus disease has remained rotaviruses but its temporal association with the first high [3,4] despite improvements in sanitation. An licensed rotavirus vaccine RotaShield, led to the explanation for this may be that improved hygienic withdrawal of the vaccine in 1999 [8]. Two new practices and oral rehydration therapy have resulted rotavirus vaccines have recently been licensed and in a greater decline of hospitalization from bacterial epidemiological studies have not shown any causal Enweronu-Laryea et al. - Rotavirus disease & intussusception’s prevalence J Infect Dev Ctries 2012; 6(2):148-155. association of these vaccines with intussusceptions (defined as ≥ 3 watery stools voided within 24 hours [9,10]. for ≤ 7 days) at any of the three hospitals met the The licensed vaccines which contain high levels inclusion criteria for the study. Children with bloody of the most common globally prevailing rotavirus stools or those whose parents did not give consent genotype G1P8 have been shown to be very effective were excluded. Sampling strategy consisted of in reducing the burden of severe rotavirus disease in continuous daily enrollment throughout the year at Europe, the United States, and Latin America [11]. DH hospital, and only daytime enrollment (except These vaccines have shown varying levels of weekends and statutory holidays) at CH and KBTH. effectiveness in Africa [12]. The differences may be Participation in the study was voluntary and no due to variations in rotavirus genotypes among incentive was given to encourage participation. regions. Geographic differences in the diversity of strains and changes in infecting strains over time in Data collection and laboratory analysis the same geographical area have been described A standard questionnaire was used to collect [13,14]. Pre-vaccine and post-vaccine introduction demographic (date of birth, age, gender, date of surveillance for circulating rotavirus strains will be hospitalization and discharge) and clinical (episodes useful for monitoring rotavirus disease patterns and of diarrhea, vomiting, fever, treatment given, the impact of vaccination. outcome) data from the parents and hospital folders. Rotavirus vaccine has not yet been introduced Data on children younger than five years with into the private and public health service in Ghana. confirmed discharge diagnosis (by ultrasonography The World Health Organization (WHO) recommends or at surgery) of intussusception during the study that countries conduct local surveillance studies prior period was collected retrospectively from the to the introduction of new vaccines [3,15]. We report pediatric surgical unit register. Data on all pediatric on the prevalence of severe rotavirus AGE, common medical hospitalizations of children younger than rotavirus genotypes, and intussusceptions in five years were collected from the admissions and Ghanaian children younger than five years old. discharges registers of the participating hospitals. Surveillance for burden of rotavirus disease, Stool samples were collected in a labeled screw- prevalent rotavirus genotypes, and association top container no later than seven days after the onset between rotavirus disease and intussusception before of the illness and stored at 4oC until they were tested introduction of vaccination will help in monitoring its by rotavirus enzyme immuno-assay (IDEIA kit, impact. DAKO Diagnostics, Cambridgeshire, United Kingdom) for detection of rotavirus antigen. Methodology Rotavirus-positive specimens were sent to the Study design Noguchi Memorial Institute of Medical Research We conducted a prospective multicentre study in reference virology laboratory for determination of a convenience sample of three hospitals within a 10- rotavirus genotype by a reverse-transcriptase kilometer radius in Accra Metropolis, Ghana’s capital polymerase chain reaction (RT-PCR) method and city, from January 2008 to December 2009. The nucleotide sequencing [16]. Quality control was population of Accra is estimated to be about four ensured by re-testing 10% of EIA-negative stool million and these three hospitals provide inpatient specimens at the reference laboratory. care to over 50% of hospitalized children in the city. Two of the chosen hospitals, Children’s Hospital Data analysis (CH) and District Hospital (DH), provide both All data were entered into a database using the primary and secondary levels of care. The third Epi Info 3.5.1 (CDC, Atlanta, Georgia, USA) and hospital, Korle Bu Teaching hospital (KBTH), analyzed with Stata version 10 (StataCorp, College provides tertiary medical care and pediatric surgery Station, TX, USA). The proportion of AGE cases services for DH and CH, and many other hospitals in among all hospitalized children younger than five the southern regions of Ghana. years was calculated for each center and overall, using as a denominator the total number of children Study population less than five years old hospitalized during the study Children younger than five years of age who period. The proportions of rotavirus gastroenteritis were hospitalized for longer than 24 hours by a among AGE hospitalizations in children younger medical officer with a primary diagnosis of AGE than five years of age and all hospitalized children 149 Enweronu-Laryea et al. - Rotavirus disease & intussusception’s prevalence J Infect Dev Ctries 2012; 6(2):148-155. Table 1. Prevalence of severe acute rotavirus gastroenteritis in children younge r than 5 years old at 3 levels of health-care delivery in participating hospitals Prevalence of rotavirus Rotavirus Hospitalizations gastroenteritis gastroenteritis < 5 years AGE* No. Stools Rotavirus hospitalizations cases (%) tested positive (%) (%) Primary level care 2040 242 (11.9) 246 105 (42.7) 5.1 Secondary level care 6182 1120 (18.1) 386 194 (50.2) 9.1 Tertiary care 8126 785 (9.7) 445 229 (51.5) 5.0 Total 16348 2147 (13.1) 1077 528 (49) 6.4 *Acute gastroenteritis younger than five years were computed. Proportions months. The peak months occurred during the dry were compared by χ2-tests, odds ratio (OR), and 95% season in 2008 and the rainy season in 2009. The confidence interval (95% CIs). seasonal pattern of rotavirus and non-rotavirus AGE during both years are shown in Figure 1. Results During the 2 years of the study, 16,348 children Age distribution younger than five years were hospitalized, and 13.1% We found that 73% of all children younger than (2147) of these cases were due to AGE. None of the five years hospitalized for AGE were less than 15 children whose stools were collected for the study months old. Among those whose stools were tested, was admitted more than once for AGE. We collected 74% (406/549) of non-rotavirus AGE and 80.3% demographic and clinical data and stool specimens (424/528) of rotavirus AGE cases occurred in from 1,080 of the 2,147 AGE hospitalizations. Three children younger than 15 months. Rotavirus AGE stool specimens were insufficient; thus 50.2% occurred less frequently than non-rotavirus AGE in (1077/2147) of the stool specimens were tested. Of children less than three months old [32/528 versus the AGE cases tested, 49% were rotavirus positive; 59/549 OR 0.54 (95% CI 0.34 – 0.84) p = 0.006]. thus 6.4% of all hospitalizations of children younger The peak age for AGE of any cause was 6 to 12 than five years could be attributed to rotavirus months. Figure 2 shows the age distribution of AGE disease. There was no significant observed difference by cause and for intussusceptions. between the prevalence of rotavirus disease among AGE cases for whom stool testing was done in 2008 Clinical features and outcome vs. 2009 {239/519 (46.1%) versus 289/558 (51.8%) There was no significant difference in the OR 1.27 (95% CI 1.0 – 1.6) p = 0.51}. severity of diarrhea and fever among children with Hospitalization for rotavirus disease was highest at rotavirus and non-rotavirus AGE as shown in Table CH, a children’s hospital. The distribution of 2. Severe vomiting and consequent use of hospitalizations and AGE cases at the participating intravenous fluid rehydration occurred more hospitals is shown in Table 1. frequently in children with rotavirus AGE (p < 0.001). Non-rotavirus AGE was associated with Seasonal distribution worse morbidity as shown by the significantly longer The proportion of AGE cases whose stools were duration of hospitalization. Thirteen children collected for analysis during the study was greater admitted with AGE died during the two years of the than 90% at DH, 45% to 52% at CH, and 50% to study, and three (23%) of these deaths occurred in 60% at KBTH for all other months except the months rotavirus-positive cases. Even though a greater of December for both years of the study when smaller proportion of children with non-rotavirus AGE died percentages of stool specimens (30% to 35%) were compared to those with rotavirus AGE, the difference collected for AGE cases. The monthly proportion of in proportions of deaths within these AGE categories all hospitalizations of children younger than five was not statistically significant (p = 0.09). years due to AGE varied from 3% to 37%. Rotavirus was isolated from the stools of more than 30% of all children hospitalized with AGE throughout the year and from more than 60% of stools during the peak 150 Enweronu-Laryea et al. - Rotavirus disease & intussusception’s prevalence J Infect Dev Ctries 2012; 6(2):148-155. Figure 1. Figure 2. 151 Enweronu-Laryea et al. - Rotavirus disease & intussusception’s prevalence J Infect Dev Ctries 2012; 6(2):148-155. Table 2. Clinical features of rotavirus and non-rotavirus severe acute gastroenteritis in children younger than 5 years old Rotavirus gastroenteritis Non-rotavirus gastroenteritis OR p value n = 528 (%) n = 549 (%) (95% CI) Episodes of diarrhea 1.1 (0.82 – 121 (22.9) 117 (21.3) 0.57 > 10/day 1.45) Episodes of vomiting 2.0 (1.44 – 113 (21.4) 65 (11.8) <0.001 >10/day 2.86) High grade fever 0.9 (0.65 – o 81 (15.3) 92 (16.7) 0.56 >38.5 C 1.25) Hospitalization 0.56 (0.40 – 74 (14) 124 (22.6) <0.001 ≥ 7 days 0.77) Mortality 0.3 (0.09 – 3 (0.6) 10 (1.8) 0.09 1.04) Intussusceptions Rotavirus disease accounted for one out of 15 (6.4%) There were 77 cases of confirmed of all hospitalized children under five years of age intussusceptions in children less than five years old and one out of two (49%) children hospitalized for during the two years of the study. There was no AGE in those studied. The incidence of 42% to association between the seasonal pattern of AGE of 51.5% at the three levels of health care in our study is any cause and intussusceptions. The majority (91%; comparable to the data from inpatient studies from 70/77) of intussusception cases occurred in children developed countries [17,18], but higher than the younger than 15 months (peak age five to eight numbers reported from other African countries [19]. months). The seasonality and age distribution of The differences may be due to the varied inclusion AGE and intussusceptions are shown in Figures 1 criteria used in the African studies. The higher and 2 respectively. prevalence in our study could be explained by the restriction of duration of illness to ≤ 7 days in our Rotavirus strains inclusion criteria; many studies in Africa enroll We tested 94.9% (501/528) of the EIA positive children up to 14 days after the onset of illness. stools for identification of rotavirus genotype. The Rotavirus shedding in children with AGE occurs most common genotypes, G1 and G2, represented maximally in the first week of the illness [20]. 61% (307/501) of all strains. G4 and G8 were the The children most affected by rotavirus and non- most uncommon strains as shown in Table 3. Of the rotavirus AGE in our study were 3 to 14 months old mixed G types, G1G2 (30%; 11/38), G1G3 (21%; and the peak age for rotavirus AGE was 6 to 12 8/38) and G1G8 (13.2%; 5/38) were the most months. The peak age occurs in older children in common. G12 was isolated in two children as developed countries and elsewhere [18,21]. Ongoing G12G10 and G12G3 mix. Of the P serotypes, P[6] surveillance in other African countries shows that was the most common during both years of the study children between the ages of three and 18 months and represented 34.5% (173/501), followed by P[8] have the highest incidence. The higher prevalence in (19.8%; 99/501), P[4] (9.4%; 47/501), mixed P types younger African children may be explained by (26.5%; 135/501) and nontypeable P types (9.4%; breastfeeding practices and unhygienic living 47/501). P[6,8] mix (34.8%; 47/135) was the most conditions. Most infants in Ghana breastfeed but common combination. About one third of (32.3%) many do not breastfeed exclusively after the age of children were infected with mixed G/P genotypes. Of three to four months. Though there has been some the non-mixed rotavirus strains, infections with improvement in hygienic practices in Ghana, G1P[8] (14.8%; 74/501) were the most common. inadequate water supply and poor sanitation facilities are still commonplace. These factors predispose Discussion many Ghanaian infants to feco-orally transmitted This study illustrates the substantial burden of gastrointestinal infections because their immune AGE in Ghanaian children younger than five years of system is too immature to handle the viral and age, especially those less than 15 months old. 152 Enweronu-Laryea et al. - Rotavirus disease & intussusception’s prevalence J Infect Dev Ctries 2012; 6(2):148-155. Table 3. Rotavirus genotypes detected from rotavirus positive stool specimens G1 G2 G3 G4 G8 G9 G10 G mix G uncharacterized Total Year 2008 86 68 23 10 1 13 5 22 17 245 Year 2009 123 30 21 0 0 6 20 16 40 256 209 98 44 10 1 19 25 38 57 501 Total (%) (41.7) (19.5) (8.8) (2) (0.2) (3.8) (5) (7.6) (11.4) (100) bacterial load from water and complementary food We found that genotypes G1 and G2 were sources [22]. common as described globally. While other Rotavirus disease occurred in more than 30% of investigators found G8 to be as common as G3 and AGE hospitalizations throughout the year. The peak G4 in Africa [19,31], our work did not confirm this. incidence occurred in the dry season in 2008 and the There were six G8 strains isolated during the two rainy season in 2009. Distinct seasonal patterns of years of the study, and five of these were G1G8 mix. peak rotavirus incidence during dry cool months have The high prevalence of P[6] in our work is similar to been described in northern Ghana [23], Kenya [24] observations of other studies from Africa. High and during the winter months in temperate regions. incidence of mixed infections has been reported from Reports from Bangladesh have also described peaks India [32]. These mixed infections may represent during cool dry months in some parts of the country naturally occurring re-assortment among rotavirus and two seasonal peaks of dry cool months and the [33]. It could also be due to rotavirus strains being monsoon season [25] as shown in this study. Other present at different concentrations thus resulting in an investigators have shown that seasonality is less uneven degree of PCR amplification that makes the marked in tropical countries [26]. interpretation of the gel band pattern difficult [34,35]. Rotavirus disease accounted for 23% of AGE Our study has some limitations. We collected related deaths in this study. Similar proportions have data from public hospitals in an urban population. been described worldwide [27]. Studies in northern The burden of disease and rotavirus genotype may be Ghana [28], a rural area, estimated that 34% of AGE different in private hospitals where high-income deaths were due to rotavirus. This higher rate of Ghanaian families usually seek medical care and in mortality as compared to our study may be attributed rural settings with inadequate health facilities. to the quality of health-care services available in rural Irrespective of these limitations, we consider our data settings. Many of these children required intravenous representative of the burden of rotavirus disease in fluid therapy because of severe vomiting and the Ghana because the majority of Ghanaians seek expertise and resources for caring for such children medical care in public health facilities. The poor may not always be available in health-care centers in collection of data in the month of December of each rural areas. More work on the burden of other non- year (mostly due to statutory holidays) of the study rotavirus pathogens that commonly cause AGE in limits any inferences we made about seasonal young Ghanaian children is needed to formulate a variations. It was difficult to accurately document comprehensive approach to reduce the morbidity and Vesikari’s scores in this study and therefore it was mortality caused by diarrheal diseases. also difficult to compare the severity of illness in our The peak age of rotavirus AGE and work with that of other studies. intussusceptions overlap but there was no correlation The substantial health burden of rotavirus disease in the seasonal pattern of the two conditions. This in Ghanaian children underscores the need for finding is similar to those of other studies [29,30]. It effective interventions for control of rotavirus disease is unlikely that there is any association between these as part of a comprehensive approach for prevention conditions but the overlap in age distribution may and control of diarrheal diseases. Rotavirus have implications for policy decisions on the age vaccination has been shown to be effective in range for rotavirus immunization in Ghanaian reducing hospitalization due to AGE of children children, even though newer rotavirus vaccines have younger than five years. We recommend the not been associated with intussusceptions. inclusion of rotavirus vaccination in the national 153 Enweronu-Laryea et al. - Rotavirus disease & intussusception’s prevalence J Infect Dev Ctries 2012; 6(2):148-155. expanded program of immunization in Ghana as an M, Ortega-Barría E, Richardson V, Rivera-Medina DM, important step for reducing the burden of AGE in Rivera L, Salinas B, Pavía-Ruz N, Salmerón J, Rüttimann R, Tinoco JC, Rubio P, Nuñez E, Guerrero ML, Yarzábal JP, children less than five years old. 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J Clin Microbiol 34: 13-121. Parashar UD, Binka F, Glass RI, Widdowson MA(2009) How much could rotavirus vaccines reduce diarrhea- Corresponding author associated mortality in northern Ghana? A model to assess Christabel C Enweronu-Laryea MRCPCH, FGCP impact. J Infect Dis 200 (Suppl 1): S85-91. Department of Child Health 29. Chouikha A, Fodha I, Maazoun K, Ben Brahim M, Hidouri University of Ghana Medical School S, Nouri A, Trabelsi A, Steele AD (2009) Rotavirus P O Box 4236 infection and intussusception in Tunisian children: Accra, Ghana implications for use of attenuated rotavirus vaccines. J Telephone: +233208154886 Pediatr Surg 44: 2133-2138. Email: chikalaryea@gmail.com 30. Chen YE, Beasley S, Grimwood K, and the New Zealand Rotavirus Study Group (2005) Intussusception and rotavirus associated hospitalization in New Zealand. Arch Dis Child Conflict of interests: No conflict of interests is declared. 90: 1077-1081. 155