Rotavirus is the leading cause of diarrhea hospitalization among children worldwide.1 Rotavirus-associated diarrhea causes over 450,000 deaths annually among children <5 years of age and 85% of the deaths occur in sub-Saharan Africa and Asia.2–4 A previous study in Kenya found that rotavirus infections caused 19% of hospitalizations and 16% of clinic visits for diarrhea among children <5 years of age and cost the health care system $10.8 million annually.5 The overall annual burden of rotavirus-associated mortality in Kenya was estimated to be 68 deaths per 100,000 children <5 years, with the highest mortality rate occurring in Nyanza Province (164 deaths per 100,000 children).5
Following trials in America and Europe that showed efficacy of over 85% against severe rotavirus infection, rotavirus vaccines, Rotarix (GSK Biologicals, Rixensart, Belgium) and RotaTeq (Merck and Co, Inc, Whitehouse Station, NJ), were introduced into routine childhood immunization programs in numerous countries.6 Several recent clinical trials evaluated the efficacy of both rotavirus vaccines in Africa and Asia, where high prevalence of malnutrition, HIV and other underlying conditions and exposures limit applicability of results of rotavirus vaccine trials conducted in developed countries. A study of Rotarix vaccine in South Africa and Malawi found an efficacy of 61% [95% confidence interval (CI): 44–73%] against severe rotavirus gastroenteritis in the first year of life.7 The RotaTeq vaccine had an overall efficacy of 64% (95% CI: 40–79%) against severe rotavirus gastroenteritis in the first year of life in 3 study sites [Kenya (Siaya district), Mali and Ghana],8 with an efficacy of 83% in the first year of life in the Kenya site. Based on the results of these trials, the World Health Organization (WHO) recommended that rotavirus vaccines be introduced into all national immunization programs, particularly where diarrheal deaths account for ≥10% of child mortality, as is the case in Kenya.6
The WHO Regional Office for Africa established the African Regional Rotavirus Surveillance Network in June 2006 to estimate the burden of rotavirus diarrheal disease in children <5 years of age and document circulating rotavirus strains in selected countries in Africa. The inclusion of western Kenya in this network in 2010 leveraged an established Health and Demographic Surveillance System (HDSS) in rural western Kenya to estimate population-based rates of rotavirus hospitalizations and deaths in children <5 years of age. Many African Regional Rotavirus Surveillance Network sites are sentinel-hospital based without a population denominator; this is 1 of the unique sites within an HDSS that can provide population-based rates. We present baseline rotavirus surveillance data from western Kenya during 2010–2011. Robust longitudinal data of rates of rotavirus-associated morbidity and mortality in Kenyan children before and after rotavirus vaccine introduction can inform national and international vaccine policies.
Rotavirus surveillance was conducted in Nyanza Province, western Kenya within the Karemo and Gem areas of the HDSS of the Kenya Medical Research Institute/Centers for Disease Control and Prevention (KEMRI/CDC). In addition to high levels of malnutrition,9 this area is holoendemic for malaria,10,11 has a high prevalence of HIV/AIDS12 and has limited access to piped water systems. This area has among the highest rates of infant and child mortality rates in Kenya. According to the HDSS, the infant mortality ratio was 87/1000 live births and the <5 mortality ratio was 171/1000 live births in 2009 (KEMRI/CDC Research and Public Health Collaboration. KEMRI/CDC Health and Demographic Surveillance System 2009, Fact Sheet. Unpublished).
Health and Demographic Surveillance System
The HDSS, established in 2001, has been described in detail previously.13,14 Briefly, the HDSS follows a defined population of approximately 220,000 residents; 16% are children <5 years of age. Trained staff conduct household interviews 3 times annually to collect birth, death, pregnancy and migration information for HDSS residents, defined as persons resident in HDSS households for ≥4 months before the interview or newborns born to the residents. Demographic data such as age/date of birth, education and occupation of head of household are gathered during initial population enumeration; household assets and occupation are updated every 2 years. The HDSS data collection also includes active morbidity surveillance in selected inpatient and outpatient health facilities for all children <13 years old and selected adults. The rotavirus surveillance described in this article encompasses residents in 2 of 3 HDSS areas, Karemo and Gem within Siaya and Gem districts with specific focus on patients visiting 3 facilities: Siaya District Hospital and Ting’wang’i Health Center (both in Karemo) and Njejra Health Center (in Gem; Fig. 1). Of patients attending these facilities, 62% of the inpatients and 97% of the outpatients were HDSS residents.
As part of the HDSS, detailed data on deaths also are collected. Deaths are captured by community-residing “village reporters” who regularly report any death in the surveillance area. In addition, community interviewers also record information on deaths during the regular thrice-yearly household surveillance visits. Verbal autopsies are conducted for all deaths, using previously described methodologies.13,15 Once these data are collected, they are coded to assign cause of death using the InterVA program, a computer algorithm software that uses a probabilistic model.16,17
Study Period and Enrollment Criteria
The surveillance was carried out from January 2010 to December 2011 in the inpatient facility of Siaya District Hospital and in the outpatient facility of Ting’wang’i Health Center. Surveillance in Njejra Health Center was carried out between June 2010 and July 2011. During these periods, all children aged <5 years, regardless of HDSS residency, visiting these facilities were eligible for enrollment if their accompanying parent or caretaker gave informed consent.
Criteria for Stool Specimen Collection
A stool specimen was collected from enrolled children who presented at the study health facilities with acute gastroenteritis (AGE), defined as ≥3 looser than normal stools and/or ≥1 episode of unexplained vomiting followed by loose stool within a 24-hour period beginning within the 7 days before seeking healthcare.
Data and Specimen Collection and Diagnostic Testing
Netbooks were used to administer a standardized questionnaire to the parents/caretaker to gather information about symptoms, medical history, laboratory investigations, diagnosis, treatment and the outcome of hospitalization. Stool was collected in a plastic diaper from which at least 2 ml of stool was scooped into a specimen container using a sterile spatula. The stool was collected within 48 hours of admission to the hospital or visit to the health facility. In the outpatient facilities, a community interviewer would follow-up with the mothers at home to collect the stool produced before 48 hours, if the child met the criteria but was unable to provide stool during the short duration of the outpatient visit. All stool samples were transported on the same day of collection to a central KEMRI/CDC enterics laboratory, approximately 60 km away, and tested for rotavirus using ELISA (Rotaclone Kit, Meridian Bioscience) methods. Voluntary counseling and HIV testing were also offered to all participants.
Data Management and Analysis
Data were stored and managed using a Microsoft SQL Server 2008 database. Statistical analysis was done using Stata 12 (Stata Corporation, College Station, TX). Comparisons of different characteristics by rotavirus positivity were made using Pearson’s χ2 test and Student’s t test, as appropriate.
Proportion of Rotavirus Infection
We calculated the proportion of stools with rotavirus AGE infection in the health facilities by dividing the number of rotavirus-positive stools by the total samples collected and tested for rotavirus.
Severity of AGE Episodes
The Vesikari scale was used to quantify the severity of AGE episodes in both the inpatient and outpatient settings. The Vesikari scale combines indicators of severity of diarrhea, vomiting, dehydration and duration of sickness to create a composite score for each episode of gastroenteritis on a scale ranging from 0 to 20; an episode of AGE with a score of ≥11 is classified as severe.18
Rotavirus-associated Hospitalization and Mortality Rates
For analyses of rates of rotavirus associated hospitalization and mortality, we limited data to children who were HDSS residents within the hospital catchment area of Karemo (Fig. 1) and those hospitalized within Siaya District Hospital. We limited rate calculations to Karemo because previous analyses suggest data on AGE hospitalizations and rotavirus AGE positivity from Siaya District Hospital to be most representative of the immediate hospital catchment area. The total person-years of observation (pyo) for HDSS residents <5 years of age was calculated as the aggregated time, for which children <5 years of age met HDSS residency requirements in Karemo during the 2-year study period, which totaled 25,009 years of observation. The crude rate of rotavirus-associated hospitalizations was then calculated by dividing the total number of <5 rotavirus-positive AGE hospitalizations by the person-time in years during the study period, multiplied by 100,000 (and presented as cases per 100,000 pyo). To account for underestimation of incidence because of patients with AGE who did not have stool tested, the crude rate was adjusted by dividing it by the proportion of inpatients meeting stool collection criteria who had a stool specimen collected and tested for rotavirus.
The rate of rotavirus-associated <5 mortality was calculated as the product of the total number of deaths among HDSS residents <5 years of age in Karemo during the 2-year study period, the proportion of <five deaths attributable to diarrhea in the area (established through verbal autopsy) and the proportion of hospitalized AGE associated with a positive rotavirus test (as a proxy for the proportion of diarrheal deaths attributable to rotavirus), as shown in the following formula19:
(Total <5 deaths among HDSS residents in study area) × (proportion of deaths attributable todiarrhea) × (proportion of hospitalized AGE episodes attributable to rotavirus) = no of deaths attributable to rotavirus
To calculate the rate (per 100,000 pyo) of <5 rotavirus mortality, we then divided the number of <5 rotavirus deaths by the total <5 pyo during this period and multiplied by 100,000.
We calculated 95% CIs around crude rates using the PEPI method20 and around the adjusted rates using the Delta method.21
Extrapolation of Rates to Nyanza Province
Using the same formulae and the total and <5 populations, the number of hospitalizations and the number of deaths reported from the 2009 census of the Kenya National Bureau of Statistics,22 we extrapolated the rates of rotavirus AGE hospitalization and rotavirus AGE mortality from the HDSS to Nyanza Province.
Over the study period, there were 4991 hospitalizations of children <5 years of age at Siaya District Hospital; 1134 (23%) met criteria for AGE. We obtained consent and stool specimens from 790 (70%). There were 4951 sick visits for children <5 years of age in the outpatient facilities (Ting’wang’i and Njejra), with 608 (12%) meeting the criteria for AGE; stool samples were collected for 320 (51%). Among all Siaya District Hospital pediatric inpatients, 3112 (62%) were from the HDSS of which 2255 (72%) were from the Karemo area (Fig. 2). Among the outpatients, 4801 (97%) were from the HDSS of which 3673 (77%) were from Karemo and visited Ting’wang’i Health Center. The proportions of AGE and stool samples collected from HDSS Karemo residents are shown in Figure 2. There were no significant differences in terms of gender or HDSS residency status, when comparing participants from whom we collected stool specimens versus those from whom we did not. However, in both the inpatient and outpatient populations, more stool was collected from the youngest patients and those with higher Vesikari scores; in the outpatient setting, stool collection was slightly more successful among HIV-uninfected patients (Table 1). Among all AGE, the proportion of stools from which rotavirus was detected ranged from 7% to 43% by month among inpatients (mean = 27%; Fig. 3A). In the outpatient clinics, the combined rotavirus positivity from both facilities ranged from 0% to 50% by month (mean = 20%; Fig. 3B).
Characteristics of Patients With AGE by Rotavirus Positivity
Rotavirus positivity did not vary by age among patients with AGE and by gender, HIV status or HDSS residency status in either the inpatient or outpatient settings. In both settings, among those tested for malaria, rotavirus positivity was approximately twice as high among AGE patients with a negative malaria test compared with those with a positive malaria test (Table 2). We observed a nonsignificant seasonality trend of rotavirus positivity among AGE inpatients over this period with peaks around January to March and July to September (Fig. 3A).
Severity of AGE Episodes
Among both inpatients and outpatients with AGE, those with signs of severe illness (Vesikari score ≥11) were twice as likely to have rotavirus-associated AGE compared with patients with less severe illness (Vesikari score <11; among inpatients, odds ratio: 2.40, 95% CI: 1.67–3.45 and among outpatients, odds ratio: 2.29, 95% CI: 1.24–4.23; Table 2). There was no significant difference in the mean length of hospitalization for rotavirus-positive (5.9 days) versus rotavirus-negative (6.0 days) AGE patients. Overall inpatient case-fatality was 3.8% among rotavirus AGE patients and 5.5% among nonrotavirus AGE patients, a nonsignificant difference (Table 2).
Burden of Rotavirus in the HDSS
Burden of <5 Rotavirus AGE Hospitalizations in the HDSS
At Siaya District Hospital, 96 HDSS-resident children <5 years of age were admitted from Karemo with AGE and tested positive for rotavirus (Fig. 2). The crude <5 rotavirus AGE hospitalization rate among HDSS Karemo residents was: 384 per 100,000 pyo (95% CI: 311–469 per 100,000 pyo). The adjusted rate, accounting for the fact that stool was successfully obtained for testing in only 68% of <5 HDSS-resident AGE admissions at Siaya District Hospital (Fig. 2) and further accounting for differences in stool collection and rotavirus positivity as a function of the Vesikari score (Karemo-specific data not shown), was 501 per 100,000 pyo (95% CI: 443–558 per 100,000 pyo). From this rate, we estimate the cumulative risk of rotavirus AGE hospitalizations by 5 years of age to be 1 in 40.
Burden of <5 Rotavirus AGE Mortality in the HDSS
A total of 820 children <5 years of age among HDSS Karemo residents were estimated to have died during the study period; verbal autopsy attributed 15.7% of the deaths to diarrhea. Among HDSS Karemo-resident children <5 years of age admitted to Siaya District Hospital with AGE during the study period, the rotavirus positivity rate was 26.1%. Thus, we estimated that out of the 820 <5 rotavirus deaths, 34 were due to rotavirus. Dividing the estimated number of <5 deaths by the relevant pyo and multiplying by 100,000, the crude rate of <5 rotavirus AGE mortality in the HDSS Karemo area was 136 deaths per 100,000 pyo (95% CI: 94–190 per 100,000 pyo). From this rate, we estimate the cumulative risk of rotavirus AGE deaths by 5 years of age to be 1 in 147.
Burden of <5 Rotavirus Hospitalizations and Mortality in Nyanza Province
We extrapolated the number of rotavirus AGE hospitalizations in Nyanza Province of western Kenya as 4363 hospitalizations per year and the number of deaths likely due to rotavirus AGE as 1184 deaths per year.
In our study population in rural western Kenya, approximately one-quarter of all hospital admissions for AGE and one-fifth of outpatient clinic visits for AGE were due to rotavirus. We demonstrated high <5 hospitalization rate (501 hospitalizations per 100,000 pyo) and mortality rate (136 deaths per 100,000 pyo) associated with rotavirus AGE in our HDSS population.
Our findings are comparable with those from a 2007 study showing 19% rotavirus positivity among children <5 years of age attending selected health facilities in Bondo district, another primarily rural district in the same region of western Kenya.5 Similar findings were observed in a HDSS population in coastal Kenya where rotavirus was detected in 22% of stools from hospitalized children with AGE.23 Other studies in Kenya have reported a wide range (6–56%) in the proportion of stools from which rotavirus was detected in both inpatient and outpatient settings.24 Other studies in inpatient hospital settings in sub-Saharan Africa have reported rotavirus positivity between 30% and 45%.25–27 In America, Asia, Europe and Middle Eastern countries, the rotavirus positivity rates have ranged from 16% to 60%.2,3,28–32 Consistent with other studies that have failed to show specific risk factors for rotavirus infection other than age,23–26 rotavirus positivity in our study was not associated with gender, HIV status or HDSS residency, underscoring the observation that rotavirus is an indiscriminate pathogen among young children.2,33,34 Children with AGE who had a positive malaria test were significantly less likely to have rotavirus infection, consistent with the observation that symptoms of malaria often include diarrhea.35,36 In the inpatient setting, although rotavirus occurred throughout the year, we observed a nonsignificant seasonality trend with peaks in January to March and August to September. Previous studies in Kenya have also reported peaks in the same months (January to March and July to September).24
Rotavirus AGE was more frequently categorized as severe, using the Vesikari scoring system, than AGE resulting from other causes in both inpatient and outpatient settings. Disproportionate association of rotavirus with more severe AGE has been noted in many studies.7,8,37,38 This further supports the importance of rotavirus prevention through immunization. Nevertheless, among inpatients, rotavirus did not appear to be more lethal than other causes of AGE hospitalization (Table 2). However, because rotavirus often causes severe dehydrating diarrhea, it is patients with rotavirus AGE, who do not access health care (or oral rehydration solutions), who are most likely to die39; many severe gastroenteritis cases do not present to the hospital.40
Monitoring rotavirus AGE within the context of an ongoing HDSS allowed us to calculate population-based measures of rotavirus burden, as few other studies in Africa have done.5,23 Based on the estimated <5 hospitalization rate associated with rotavirus AGE in our HDSS population and data from the 2009 Kenyan census, we extrapolated to a high number of rotavirus-associated hospitalizations in Nyanza Province: 4363 hospitalizations per year. Furthermore, we estimated that by 5 years of age, a child would have a 1 in 40 chance of having had hospitalization due to rotavirus AGE and a 1 in 147 chance of having died due to rotavirus.
We also found high rates of mortality due to rotavirus in our HDSS population, which on extrapolation to the whole of Nyanza Province, suggested that 1220 deaths are likely due to rotavirus AGE per year. The <5 rotavirus AGE mortality rate of 136 deaths per 100,000 pyo represents approximately 4.1% of all <5 deaths in the area which is comparable with the average global estimate of 5% . In 2007, in Bondo, western Kenya, Tate et al5 estimated population-based mortality due to rotavirus as 164 deaths per 100,000 persons per year. In Kilifi, Kenya, population-based rotavirus mortality was calculated as 478 per 100,000 pyo.23 In other countries in Africa, mortality rate estimates for rotavirus AGE have ranged between 100 and 500 deaths per 100,000 children per year.2 While similar or higher levels of incidence of rotavirus infection have been shown from developed countries, greater severity of illness and deaths are more likely in developing countries.3,27–33,41 In Europe, Canada and the United States, the average stool rotavirus positivity rate ranged between 37% and 40 %, but the rotavirus-associated mortality rate was estimated to be <10 per 100,000. This discrepancy between incidence and mortality rates in developed and developing countries is likely due to the fact that many children with severe rotavirus AGE in developing countries never receive proper treatment. We previously found in the same area that for every severe rotavirus AGE case presenting in the clinic, 6 cases occurred in the community.39
The findings of this study suggest that introduction of rotavirus vaccine in Kenya could substantially reduce AGE morbidity among young children. A rotavirus vaccine with efficacy in the range of that reported for Rotarix and RotaTeq in Africa (61–64% efficacy)7,8 and with 74% vaccination coverage during the first year of life (the average for other routine childhood immunizations in our study area),10 could prevent approximately 12% of hospitalizations due to AGE in children <5 years of age in western Kenya, many of which occur in children <2 years of age. Using the above efficacy levels for the vaccines, and that the pediatric vaccination coverage is 65% in Nyanza Province,9 we estimate that rotavirus vaccine could reduce <5 AGE hospitalization province-wide by at least 10%, which would translate to 436 fewer <5 hospitalizations annually.
This study had important limitations. First, all eligible stool samples were not collected, due to refusal to give consent or delays in collecting stool until after 48 hours had elapsed. This occurred more in the outpatient facilities and may have resulted in missing positive or negative samples; we collected stool samples at home to mitigate this. In addition, we adjusted our burden estimates to account for the difference in stool collection by severity of illness among inpatients. Second, we focused our recruitment of participants from sentinel health facilities; thus, we may have missed rotavirus cases among those who failed to come to the facilities and for which mortality may be more likely (because of lack of access to lifesaving rehydration). As such, our study does not represent the community morbidity burden of rotavirus AGE.
In conclusion, rotavirus is a common cause of gastroenteritis among children <5 years of age seeking care as inpatients and as outpatients in rural western Kenya, and the population-based burden of rotavirus-associated hospitalization and mortality in this setting is high. These data reinforce the need for accelerated introduction of rotavirus vaccine in Kenya. Continued monitoring of rotavirus-associated disease in the KEMRI/CDC HDSS in Siaya district, in particular with additional linkages between community and health facility surveillance data, will provide the Government of Kenya and international policy makers with timely and accurate data on the population-level impact of rotavirus vaccine introduction in rural western Kenya.
The authors would like to acknowledge the HDSS and hospital community where they carry out the surveillance activities. The authors also acknowledge the support offered by Dr. Omoto, Dr. Onditi and other staff at the Siaya District Hospital. The authors acknowledge the support received from the Division of Disease Surveillance and Response of the Kenya Ministry of Public Health and Sanitation, staff in the field and data room at KEMRI/CDC and the WHO Regional Office for Africa. This article is published with the approval of the Director of KEMRI. KEMRI/CDC is a member of the INDEPTH Network.
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