Impact of Rotavirus Vaccination on Diarrheal Hospitalizations in Children Aged <5 Years in Lusaka, Zambia

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1 Clinical Infectious Diseases SUPPLEMENT ARTICLE Impact of Rotavirus Vaccination on Diarrheal Hospitalizations in Children Aged <5 Years in Lusaka, Zambia Evans M. Mpabalwani, 1 Chibumbya J. Simwaka, 2 Jason M. Mwenda, 3 Cynthia P. Mubanga, 2 Mwaka Monze, 2 Belem Matapo, 4 Umesh D. Parashar, 5 and Jacqueline E. Tate 5 1 Department of Paediatrics and Child Health, and 2 Virology Laboratory, University Teaching Hospital, Lusaka, Zambia; 3 World Health Organization, Regional Office for Africa, Brazzaville, Republic of Congo; 4 World Health Organization Country Office, Lusaka, Zambia; and 5 Centers for Disease Control and Prevention, Atlanta, Georgia Background. Monovalent rotavirus vaccine was introduced in the routine public health immunization program in Lusaka, Zambia, in January 2012 and was rolled out countrywide in November We examined the effect of rotavirus vaccination on hospitalization for all-cause acute gastroenteritis (AGE) and rotavirus-specific AGE at a large referral hospital in Lusaka. Methods. Data were derived from ongoing hospital-based AGE surveillance from January 2009 to December Pre rotavirus vaccine introduction ( ) and post rotavirus vaccine introduction ( ) periods were compared for annual changes in hospitalizations for AGE and rotavirus; 2012 was excluded as a transition year. Hospital administrative discharge data were used to compare trends in all-cause diarrhea discharges and in-hospital diarrhea deaths captured by HIMS pre- and post rotavirus vaccine introduction. Results. Between January 2009 and December 2014, 5937 children <5 years of age presenting with AGE had their stools collected and tested for rotavirus by enzyme immunoassay. The rotavirus positivity rate declined from 40.1% (449/1121) in prevaccine years to 30.2% (250/828; P <.001) in 2013 and 24.7% (157/635; P <.001) in The greatest reduction was noted in infants, with the rotavirus positivity rate in this age group declining from 40.9% in prevaccine years to 34.0% (P =.009) in 2013 and 26.2% (P <.001) in Following rotavirus vaccine introduction, seasonal peaks of rotavirus and all-cause AGE were dwarfed. From HIMS data, compared to the prevaccine era, reductions of 18% 29% in all-cause diarrhea hospitalizations and 27% 33% in-hospital diarrhea deaths among children <1 year of age were observed in 2013 and Conclusions. We observed a significant reduction in AGE-associated in-hospital morbidity and mortality following rotavirus vaccine introduction. The greatest reduction was seen in infants <1 year who accounted for 84.4% of rotavirus hospitalizations prior to vaccine introduction. Keywords. acute gastroenteritis; rotavirus vaccine; impact; disease burden. Rotavirus is the most common cause of severe acute gastroenteritis (AGE) in young children. With the introduction of rotavirus vaccine in routine public health immunization programs [1, 2], declines in the burden of severe childhood AGE have been documented in early vaccine-introducing countries, such as the United States [3 5], Australia [6], and several countries in South America [7 9] and Europe [10, 11]. Rotavirus vaccines are expected to have the highest impact on AGE morbidity and mortality in Africa, where the burden of disease is the greatest [2], but data from African countries on vaccine impact are sparse given the more recent introduction of vaccines in the region. Given the lower efficacy of rotavirus vaccines in developing countries compared with developed countries in clinical trials [12], assessing impact of routine rotavirus vaccination in developing settings is important. Correspondence: E. M. Mpabalwani, University Teaching Hospital, Department of Paediatrics and Child Health, PO Box 50001, Lusaka, Zambia (evansmwila@gmail.com). Clinical Infectious Diseases 2016;62(S2):S183 7 The Author Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, journals.permissions@oup.com. DOI: /cid/civ1027 The Zambian government through the Ministry of Community Development, Mother and Child Health with the assistance of Gavi, the Vaccine Alliance rolled out an oral monovalent rotavirus vaccine (Rotarix; GlaxoSmithKline Biologicals) countrywide in November 2013 [13]. The vaccine was initially introduced in Lusaka province as a pilot demonstration project in January 2012 [13] (E.M.Mpabalwani,C.J.Simwaka,M. Monze,B.Matapo,J.M.Mwenda,unpublisheddata).The monovalent rotavirus vaccine is given at 6 and 10 weeks of age (without a catch-up dose) together with oral polio vaccine types 1 and 2, respectively. The first dose of monovalent rotavirus vaccine is administered early in life (6 weeks) due to early exposure of rotavirus infection [2] (E. M. Mpabalwani, C. J. Simwaka, M. Monze, B. Matapo, J. M. Mwenda, unpublished data). Rotavirus surveillance among children admitted with AGE has been in existence at the University Teaching Hospital (UTH) in Lusaka since In this study, we report the early impact of rotavirus vaccine introduction on all-cause diarrhea and rotavirus AGE hospitalizations and in-hospital deaths for diarrhea at the UTH in Lusaka, Zambia. Rotavirus Vaccination CID 2016:62 (Suppl 2) S183

2 Patients and Methods UTH is a 2000-bed hospital with >500 bed spaces in the Department of Paediatrics and Child Health. More than 95% of the patients attended to in the Department are referred from community district hospitals in the greater city of Lusaka, which has an under-5 population of about (E. M. Mpabalwani, C. J. Simwaka, M. Monze, B. Matapo, J. M. Mwenda, unpublished data). The period from January 2009 to December 2011 was defined as the pre vaccine introduction period and the period from January 2013 to December 2014 was defined as the post vaccine introduction period. The year 2012 was excluded as a transition year with low vaccine uptake. Active Surveillance A suspected case of rotavirus AGE was definedasachild<5 years of age who was hospitalized for treatment of acute watery diarrhea and/or vomiting of <7 days duration [14]. Children aged <5 years hospitalized for AGE were recruited to the surveillance for rotavirus by dedicated research nurses under the guidance of a pediatrician. Demographic and clinical data were collected using a case investigation form adapted from World Health Organization generic guidelines for rotavirus surveillance. A stool sample was collected within 48 hours of admission and transported to the virology laboratory within 24 hours. Stool samples were tested for group A rotavirus using an enzyme immunoassay (EIA; Dako). Discharge Data Hospital discharge administrative data for all-cause diarrhea discharges and in-hospital diarrhea deaths for children <1 year of age were abstracted from the hospital s HIMS.These data are routinely captured from case files on discharge/death on the wards daily and aggregated weekly and monthly by the HIMS unit. The summarized data are entered into a computer database using discharge codes of the International Classification of Diseases, Tenth Revision (ICD-10). The ICD-10 codes used were A00.9 (cholera, unspecified), A03.9 (shigellosis, unspecified), A09 (infectious gastroenteritis and colitis, unspecified), and K52.9 (noninfective gastroenteritis and colitis, unspecified). Data Analysis Data were analyzed using Epi Info version We analyzed AGE hospitalizations due to rotavirus before and after the vaccine was introduced. We also examined total hospital admissions for diarrhea pre and post vaccine introduction and calculated the percentage of decline in all-cause diarrhea hospitalizations and in-hospital diarrhea deaths. We used Microsoft Excel to calculate the median number of tests performed and number of positive tests pre vaccine introduction. We examined the percentage of decline in the total number of samples tested and the number rotavirus positive before and after the vaccine was introduced. We also calculated the percentage of decline in proportions that were rotavirus positive before and after the vaccine was introduced and compared the proportions positive using χ 2 tests. RESULTS Active Surveillance Data From January 2009 through December 2014, 5936 children <5 years of age with AGE were enrolled in active surveillance, and 5853 (98.6%) had their stools tested for rotavirus by EIA. In the pre rotavirus vaccine introduction period ( ), a median of 40.1% (449/1121) of children with AGE tested positive for rotavirus annually (Table 1). In the post rotavirus vaccine Table 1. Number and Percentage of Decline in Children Tested, Number Testing Rotavirus Positive, and the Proportion Rotavirus Positive Before ( ) and After (2013 and 2014) Rotavirus Vaccine Introduction, University Teaching Hospital, Lusaka, Zambia Age Total Tested No. Positive % Positive Total Tested No. Positive Proportion Positive <5 y of age Median <1 y of age Median y of age Median y of age Median S184 CID 2016:62 (Suppl 2) Mpabalwani et al

3 Figure 1. Rotavirus positivity by age group before ( ) and after (2013 and 2014) vaccine introduction, University Teaching Hospital, Lusaka. period, the rotavirus positivity rate declined to 30.2% (250/828; P <.001) in 2013 and to 24.7% (157/635; P <.001) in 2014 (Figure 1). The declines in rotavirus positivity rates were associated with a corresponding decline in the total number of children tested and the number of children with a positive result (Table 1). The greatest reduction in rotavirus positivity between the pre and post rotavirus vaccine introduction was noted in infants <12 months of age (Table 1 and Figure 1). Compared with the prevaccine median rotavirus positivity rate of 44.6%, the rotaviruspositive rate declined to 34.0% (P =.009) in 2013 and 26.2% (P <.001) in 2014 (Table 1). Smaller declines in the total number of children enrolled and the number rotavirus positive, and the percentage rotavirus positive were observed in children 1 year of age. No declines were observed in children 2 4 years of age. Prior to rotavirus vaccine introduction, 84.4% (1133/1342) of rotavirus-positive cases occurred in children <1 year of age, 14% (195/1342), occurred in children 1 year of age, and 0.9% (13/1342) occurred in children 2 4 years of age. Post rotavirus vaccine introduction in 2013 and 2014, 75.1% (307/409; P <.001) of rotavirus-positive cases occurred in children <1 year of age, 21% (86/409; P =.002) occurred in children 1 year of age, and 3.9% (16/409; P <.001) occurred in children 2 4 years of age. Prior to vaccine introduction, rotavirus AGE exhibited a distinct seasonality, usually with 2 obvious peaks of rotavirusassociated diarrhea during the months of May June and September October. Following rotavirus vaccine introduction, seasonal peaks of rotavirus and all-cause AGE were dwarfed, especially the smaller peak toward the end of the year (Figure 2). Figure 2. Seasonality of rotavirus diarrhea, University Teaching Hospital, Lusaka, January 2009 December Rotavirus Vaccination CID 2016:62 (Suppl 2) S185

4 Figure 3. All-cause diarrhea and in-hospital diarrhea deaths before ( ) and after (2013 and 2014) rotavirus vaccine introduction among children <1 year of age, University Teaching Hospital. All-cause diarrhea as shown by International Classification of Diseases, Tenth Revision codes: A00.9, A03.9, A09, K52.9. Discharge Data A reduction in all-cause diarrhea hospitalizations and in-hospital deaths among children <1 year of age was also observed in the post rotavirus introduction era (Figure 3). All-cause diarrhea hospitalizations declined 29% in 2013, from a median of 1143 in to 817, and 18% to 942 in Similarly, a reduction of 27% and 33% among in-hospital deaths for all-cause diarrhea among children <1 year of age occurred in 2013 (from 114 to 83) and in 2014 (from 114 to 76), respectively, compared to the pre vaccine introduction median from 2009 to DISCUSSION Following the introduction of monovalent rotavirus vaccine in January 2012, all-cause diarrhea and rotavirus AGE hospitalizations as well as in-hospital diarrhea deaths declined at a large referral hospital in Lusaka, Zambia, over 2 consecutive postvaccine years (2013 and 2014). These overall declines were associated with a blunting of the characteristic seasonal peaks of rotavirus AGE in Zambia, further supporting that the declines are attributable to the effect of vaccination. The monovalent rotavirus vaccine coverage in infants was 39% in 2013 and 77% in 2014 in Lusaka district (Lusaka Provincial Health Office, Ministry of Health, Zambia, personal communication). As the coverage rates of 2 doses of rotavirus vaccine reach the oral polio vaccine type 2 coverage of 83% (2014), we anticipate even greater declines in the burden of severe AGE in Zambian children. The declines in rotavirus AGE were particularly evident in infants, in whom a marked reduction was observed in the rotavirus positivity rate from 44.6% to 26.2% in the pre and post rotavirus vaccine eras, respectively, representing a reduction of 51%. As rotavirus disease burden, including mortality, is highest in infants in low-resource countries (E. M. Mpabalwani, C. J. Simwaka, M. Monze, B. Matapo, J. M. Mwenda, unpublished data) [15 17], this decline is particularly noteworthy. In 1-yearolds, rotavirus positivity rates also declined by 31.4% from prevaccine vs postvaccine years. Although rotavirus positivity rates increased post vaccine introduction in children 2 4 years of age compared with prevaccine year, this age group only accounted for 1% of all rotavirus hospitalizations in the prevaccine era. Thus, this increase in older children is not particularly concerning, but should be further monitored, particularly as vaccine coverage increases in older children. Rotavirus vaccine implementation has been associated with a reduction in all-cause AGE mortality in several middle-income countries in the Americas [7 9]. Our analyses of administrative data are among the first to demonstrate a potential impact of vaccination on in-hospital diarrhea mortality in African children. We observed a reduction of 27% and 33% in 2013 and 2014, respectively, compared to prevaccine years. An ecological observational study such as ours has a number of limitations. First, the observed reduction in all-cause diarrhea did not take into account seasonal trends of other causes of diarrhea or other interventions that may have impacted diarrhea hospitalizations [6, 9, 15]. Nonetheless, our data have demonstrated significant reductions in rotavirus AGE and all-cause diarrhea hospitalizations, and we attribute these declines to S186 CID 2016:62 (Suppl 2) Mpabalwani et al

5 rotavirus introduction in the routine public health immunization program. The investigators had no control on the quality of the hospital administrative data, but the data were robust enough to support reductions in all-cause diarrhea. However, the quality of these data needs to be improved. Finally, our study has not evaluated rotavirus vaccine immunization status of each individual child. In conclusion, within 2 years following rotavirus vaccine introduction in Lusaka, Zambia, we observed a significant decline in all-cause AGE morbidity and mortality at a large referral hospital in Lusaka. The greatest reductions were seen in children <1 year of age, who accounted for 84.4% of rotavirus hospitalizations in this age group prior to vaccine introduction. Our data support the financial investment in rotavirus vaccine by the government of the Republic of Zambia and should encourage other low-income countries to consider adopting rotavirus vaccination for prevention of severe childhood AGE. Notes Acknowledgments. The authors acknowledge Gavi, the Vaccine Alliance for financial support to the World Health Organization to support new vaccine surveillance, and support from the Ministry of Community Development, Mother and Child Health through the National Expanded Programme on Immunization. We also thank the Ministry of Health through the UTH management for the support and for creating a hospital environment conducive to carrying out new vaccine surveillance. We also thank the children and their parents/guardians who have continued to participate in rotavirus disease surveillance study since The research nurses on the ward deserve credit for their dedication in recruiting children with AGE to the study. Disclaimer. The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC). The views expressed by the authors do not necessarily reflect the views of PATH, the CDC Foundation, the Bill and Melinda Gates Foundation, or GAVI, the Vaccine Alliance. Supplement sponsorship. This article appears as part of the supplement Health Benefits of Rotavirus Vaccination in Developing Countries, sponsored by PATH and the CDC Foundation through grants from the Bill and Melinda Gates Foundation and GAVI, the Vaccine Alliance. Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Patel M, Steele D, Gentsch JR, Wecker J, Glass RI, Parashar UD. 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