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Impact of rotavirus vaccination on childhood gastroenteritis-related mortality and hospital discharges in Panama
International Journal of Infectious Diseases 16 (2012) e94–e98
Contents lists available at SciVerse ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Impact of rotavirus vaccination on childhood gastroenteritis-related mortality and hospital discharges in Panama Vicente Bayard a,*, Rodrigo DeAntonio b, Rodolfo Contreras a, Olga Tinajero c, Maria Mercedes Castrejon b, Eduardo Ortega-Barrı´a d, Romulo E. Colindres d a
Instituto Conmemorativo Gorgas de Estudios de la Salud, Avenida Justo Arosemena Calle 35, APDO 0816-02593, Panama City, Panama GlaxoSmithKline Biologicals, Panama City, Panama Instituto de Investigaciones Cientı´ficas y Servicios de Alta Tecnologı´a (INDICASAT), Panama City, Panama d GlaxoSmithKline Biologicals, Rio de Janeiro, Brazil b c
A R T I C L E I N F O
S U M M A R Y
Article history: Received 21 July 2011 Accepted 6 September 2011
Background: Rotavirus vaccination was introduced in Panama in March 2006. This study was carried out in order to describe the trends in gastroenteritis-related (GER) hospitalizations and mortality in children <5 years of age during the pre- and post-vaccination periods. Methods: Data from the Expanded Program on Immunization (Ministry of Health) were used to calculate vaccine coverage. GER mortality and hospitalizations were obtained through database review of the Contralorı´a General de la Repu´blica and hospital discharge databases of five sentinel hospitals, for the period 2000–2008. Mean rates of GER mortality and mean numbers of hospitalizations during the baseline pre-vaccination period (2000-2005) were compared to those of 2007 and 2008. Results: National coverage for the second rotavirus vaccine dose increased from 30% in 2006 to 62% in 2007 and 71% in 2008, varying from 62% in the West region to 77% in the Panama region. Overall, at 2years post-vaccine introduction, the GER mortality rate in Panama had decreased by 50% (95% confidence interval (CI) 46–54). During 2000–2005, the GER mortality rate in children (<1 year) was 73/ 100 000, decreasing by 45% (95% CI 40–51) in 2008. In children aged 1–4 years, the GER mortality rate was 20.3/100 000 (2000–2005), decreasing by 54% (95% CI 48–60) in 2008. The Panama region registered the highest mortality rate reduction (69%; 95% CI 58–81) for 2008. During 2008, GER hospitalizations among children <5 years of age decreased by 30% (95% CI 21–37) from the mean number of hospitalizations during 2000–2005. Conclusions: A substantial reduction in GER mortality and hospitalizations was observed following the introduction of rotavirus vaccine in Panama. ß 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: William Cameron, Ottawa, Canada Keywords: Gastroenteritis Rotavirus vaccine Gastroenteritis-related deaths Gastroenteritis-related hospitalizations
1. Introduction Globally, rotavirus (RV) is the most common cause of acute diarrhea requiring hospitalization among infants and young children. Annually, rotavirus has caused over 611 000 deaths (range 454 000–705 000), approximately 2.4 million hospitalizations, and over 25 million clinic visits worldwide among children <5 years of age;1–3 more than 85% of these deaths occur in lowincome countries of Asia and Africa.4 The case fatality rate is often higher among children in low-income countries,5 though its incidence is similar in developed and developing countries.5,6 As per the World Health Organization (WHO) rotavirus surveillance network, approximately 40% (range 10–59%) of diarrhea hospita-
* Corresponding author. Tel.: +507 5274811; fax: +507 5274889. E-mail address: [email protected] (V. Bayard).
lizations among children <5 years of age worldwide, and 34% (range 10–51%) in the region of the Americas, were attributed to rotavirus infection prior to vaccine introduction.7 In Latin America, over 15 000 deaths, 75 000 hospitalizations, and 10 million cases of rotavirus diarrhea were reported annually.4 In Panama, prior to vaccine introduction, an estimated 15% of infants <6 months of age and 85% of infants <1 year old had had at least one episode of rotavirus infection.8 In order to reduce the global disease burden due to rotavirus gastroenteritis, effective and safe vaccines have been developed2,3,9,10 and are now recommended by the WHO for inclusion in national immunization programs.9 Two oral rotavirus vaccines are available in more than 100 countries worldwide: a two-dose TM human-attenuated rotavirus vaccine RIX4414 (Rotarix ; GlaxoSmithKline Biologicals, Rixensart, Belgium) and a three-dose live TM pentavalent bovine–human reassortant vaccine (Rotateq ; Merck, Whitehouse Station, NJ, USA). Both vaccines have demonstrated an
1201-9712/$36.00 – see front matter ß 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2011.09.003
V. Bayard et al. / International Journal of Infectious Diseases 16 (2012) e94–e98
established efficacy against severe rotavirus disease (85–98%) and against all-cause acute gastroenteritis (42–59%) in clinical trials.11,12 Based on these encouraging results, some of the countries of Latin America, including Brazil, Venezuela, El Salvador, and Mexico, have introduced rotavirus vaccines into their national programs (up until 2007).13 In March 2006, Panama introduced the human-attenuated rotavirus vaccine into its Expanded Program on Immunization (EPI) for the entire Panamanian birth cohort (70 000 children per year) using a two-dose scheme for children under 6 months.14 The WHO recommends that vaccine impact be assessed by monitoring trends in hospitalizations and mortality from all-cause acute gastroenteritis using secondary data sources.15 Following the introduction of rotavirus vaccines into immunization programs, global rotavirus surveillance networks were established to monitor the performance of the vaccines.13,16 The present study was undertaken to evaluate gastroenteritis-related (GER) hospitalizations and mortality trends in children <5 years of age before and after the introduction of rotavirus vaccination in Panama. 2. Methods Data on the number of rotavirus vaccine doses administered as first and second doses by region were obtained from the EPI of the Panamanian Ministry of Health. Vaccine coverage was calculated for the age group <1 year using the population estimated by the census as the denominator and stratified by region, as follows: (1) West region (Bocas del Toro, Chiriquı´, and Comarca Ngo¨be Bugle´), (2) Central region (Cocle´, Herrera, Los Santos, and Veraguas), (3) Panama region (East Panama, West Panama, Metropolitan Panama, and San Miguelito), and (4) Northeast region (Colo´n, Darie´n, and Comarca Kuna Yala). National mortality data for GER outcomes in children <5 years of age during 2000–2008 were obtained from the Contralorı´a General de la Repu´blica (CGR) databases. The Vital Statistics Department of CGR from Panama is responsible for data on main/ primary cause of death obtained from death certificates, and has an estimated coverage of >85% of all deaths reported in Panama. Mortality data are recorded at the municipality level, reported, reviewed, and entered into the province database, and transmitted electronically to the national level. Data from the CGR are the recognized official national mortality data. There are 13 main hospitals nationwide providing pediatric medical care (two tertiary care and 11 secondary care hospitals). We reviewed the databases of the main five hospitals representing different settings in Panama (three urban hospitals: Hospital del ˜ o, Hospital de Especialidades Pediatricas, Hospital San Miguel Nin Arcangel; one suburban: Hospital Nicolas Solano; and one rural: Hospital de Changuinola), which are considered as reference hospitals for pediatric care across the country. Both GER mortality and hospitalization data were collected using the International Classification of Diseases, 10th revision (ICD-10), including diarrhea and gastroenteritis of presumed infectious origin (A09X). Annual GER mortality rates were calculated using the population estimates from population data in the census as the denominator. The mean rate of GER mortality and number of hospitalizations during 2000–2005 was used as the baseline against which to compare the post-vaccination years (2007 and 2008). As rotavirus vaccine was introduced in Panama in early 2006, this year was considered a transitional year and excluded from the analysis. The absolute and relative reduction in deaths and mortality rates were computed with 95% confidence intervals (CI) using the exact Poisson confidence limit.17 Analysis was stratified according to age groups <1 year and 1–4 years and by region. All statistical analyses were performed using SAS v. 9.1, Epi Info v. 3.4.3, and Microsoft Excel.
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3. Results 3.1. Rotavirus vaccine coverage A total of 284 328 rotavirus vaccine doses, 60% as first doses and 40% as second doses, were administered between March 2006 and December 2008 to children aged <1 year in Panama. Vaccine coverage of the first dose in children <1 year of age was 62% in 2006, 89% in 2007, and 91% in 2008, while second dose coverage was 30%, 62%, and 71%, respectively. Vaccine coverage varied across regions. The Panama region had the highest two-dose coverage in the country, with 70% in 2007 and 77% in 2008, in comparison to the other regions, as shown in Figure 1. However, all regions showed an increase in vaccine coverage over time for both doses. 3.2. GER mortality From 2000 to 2008, 883 GER deaths were reported among children <5 years of age in Panama; 424 (48%) in children <1 year of age and 459 (52%) in children aged 1–4 years. The mean number of GER deaths in children <5 years of age during the prevaccination period of 2000–2005 was 103 (95% CI 92–112). Most of these cases occurred in the West region (60%). All regions reported a reduction in the number of GER deaths in children <5 years of age during 2008, with the highest reduction in the Panama region (66%; 95% CI 55–72) and the lowest reduction in the Northern region (33%; 95% CI 12–52) (Figure 2). Overall, the number of deaths in children <5 years of age was reduced by 47% (95% CI 41– 52). The absolute number of GER deaths in children aged <1 year and 1–4 years decreased from a mean of 49 and 54, respectively, during the pre-vaccination period, to 28 (43%; 95% CI 38–47) and 26 (51%; 95% CI 43–58), respectively, during 2008. Trends in the GER mortality rate are presented in Figure 3. The GER mortality rate in children under 5 years of age during 2000– 2005 was 31.1 per 100 000 children and decreased by 50% (95% CI 46–54) in 2008, with a rate of 15.5 per 100 000 children (Table 1). The highest mortality rate prior to vaccine introduction was observed in the West region, with a mean of 79.9 per 100 000 children, decreasing by 48% (95% CI 43–52) in 2008. The Panama region registered the highest reduction in mortality rate of 69% (95% CI 58–81) for 2008. In children <1 year of age, the GER mortality rate during 2000–2005 was 73 per 100 000 children, decreasing by 45% (95% CI 40–51) during 2008. In children 1–4 years of age, the GER mortality rate during 2000–2005 was 20.3 per 100 000 children, decreasing by 54% (95% CI 48–60) in 2008. 3.3. GER hospitalizations During 2000–2008, a total of 26 700 GER hospitalizations were observed in children <5 years of age at the five pediatric hospitals included in this study. During the pre-vaccination period (2000– 2005), 18 021 GER hospitalizations were observed in children <5 year of age, with a mean of 3004 hospitalizations per year (95% CI 2671–3336) during 2000–2005, decreasing by 4% (95% CI 8–13) and 30% (95% CI 21–37) in 2007 and 2008, respectively. Over 67% of GER hospitalizations in children <5 years of age were at the ˜ o during the pre-vaccination period, the main Hospital del Nin reference pediatric hospital in Panama, in which reductions of 36% (95% CI 10–50) in 2007 and 43% (95% CI 19–55) in 2008 were observed. Among children <1 year of age, 6372 GER hospitalizations were observed during 2000–2005, with a mean of 1062 (95% CI 913– 1210) hospitalizations per year, decreasing by 7% (95% CI 1–18) in 2007 and 28% (95% CI 4–17) in 2008. In children 1–4 years of age, 11 649 GER hospitalizations occurred during 2000–2005, with a
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V. Bayard et al. / International Journal of Infectious Diseases 16 (2012) e94–e98
Figure 1. Vaccine coverage (%) in children <1 year of age by vaccine dose and region, Panama, 2006–2008. (Source: Vaccination information from the Expanded Program on Immunization (EPI) of the Ministry of Health in Panama; population data provided by the Directorate of Statistics based on the population census of the CGR).
mean of 1942 per year (95% CI 1702–2180) and reductions of 2% (95% CI 11–13) in 2007 and 31% (95% CI 20–38) in 2008 (Figure 4).
4. Discussion The present study used secondary data sources to monitor trends in GER morbidity and mortality in children <5 years of age, before and after the introduction of the human-attenuated rotavirus vaccine into the EPI in Panama in March 2006. In 2008, just 2 years after national rotavirus vaccine introduction, a substantial reduction in the number of GER hospitalizations (30%) and deaths (47%) was observed, compared to the baseline prevaccination period. This decline was most pronounced in the Panama region where vaccine coverage was the highest, suggesting the likely impact of rotavirus vaccination. The number of children receiving the first dose of the rotavirus vaccine was more than the number receiving both doses in all regions in the study. Vaccine coverage for two doses during the first year following the introduction of the rotavirus vaccine in children aged <1 year (2006) was only 30%. Nevertheless, this coverage increased to 62%
in 2007 and 71% in 2008, leading to trends in reduction in the number of GER hospitalizations and deaths. A decrease in GER mortality rate by 45% (95% CI 40–51) was observed in children <1 year of age and by 54% (95% CI 48–60) in children 1–4 years of age during 2008, compared to the baseline pre-vaccination period. These findings are consistent with data from Mexico where a decline in the diarrhea-related mortality rate of 41% for children aged <1 year and 29% for those children aged 1– 2 years was observed after the introduction of the humanattenuated rotavirus vaccine.18A decreasing trend in GER mortality rates was observed in 2007 in the Central and Panama regions, 1 year after the introduction of the rotavirus vaccine. However, mortality rates did not show a significant reduction in the West and Northeast regions during 2007, probably because these regions are inhabited by large migrant indigenous communities with more limited access to medical care, poor sanitation, and low vaccine coverage, making them more susceptible to infectious diseases. A phase III clinical trial of the human-attenuated rotavirus vaccine in Latin America showed that all-cause GER hospitalizations were reduced by 39%,11,19 suggesting rotavirus vaccination
Figure 2. Number of gastroenteritis-related deaths among children aged <5 years pre- and post-rotavirus vaccination by region, Panama. (Source: Mortality data provided by CGR in Panama; population data provided by the Directorate of Statistics based on the population census of the CGR; vaccination information obtained from the Expanded Program on Immunization (EPI) of the Ministry of Health in Panama. Note: The mean baseline value is the mean number of GERD for the baseline period 2000–2005).
V. Bayard et al. / International Journal of Infectious Diseases 16 (2012) e94–e98
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Figure 3. Trends over-time for gastroenteritis-related mortality rate by age group in Panama (2000–2008). aChi-square test for linear trend p < 0.05; bChi-square test for linear trend p = 0.07. (Note: The gray line indicates when the human-attenuated rotavirus vaccine was introduced in 2006. Source: Mortality data provided by CGR in Panama; population data provided by the Directorate of Statistics based on the population census of the CGR.).
Table 1 Gastroenteritis-related mortality rate (per 100 000) in Panama (2007 and 2008) compared with baseline period (2000–2005), by age group Age group
<1 year 1–4 years Overall
Baseline pre-vaccination period (2000–2005)
2007
Mean mortality rate
Mortality rate
% Reduction (95% CI)
2008 Mortality rate
% Reduction (95% CI)
73 20.3 31.1
77 20.2 31.7
5 ( 7 to 4)a 0.5 ( 0.7 to 0.8)a 1.9 ( 1 to 3)a
40 9 15.5
45 (40 to 51)b 54 (48 to 60)b 50 (46 to 54)b
Source: Mortality data provided by CGR in Panama. Population data provided by the Directorate of Statistics based on the population census of the CGR. a p > 0.05. b p < 0.05.
plays a major role in reducing disease burden due to gastroenteritis. In Panama, the number of GER hospitalizations in 2008 decreased by 28% in children aged <1 year and 31% in those aged 1–4 years, compared to the pre-vaccination period. A recent study in Brazil has reported a reduction of approximately 48% in hospitalizations among children <1 year of age.20 The reduction in GER hospitalizations among children aged 1–4 years suggests a possible herd protection effect.9,21 The annual report of the Ministry of Health of Panama did not document any important changes with regards to interventions in
sanitation, hygiene, or nutrition during 2007 and 2008 compared to 2000–2005, thus it is likely that the decrease in GER outcomes is an effect of vaccine introduction.22 Nonetheless, several caveats must be considered when interpreting our findings. First, we had limited access to data due to the lack of electronic records for hospital discharges and also potential under-reporting of mortality data in some regions. Second, this was an ecological study that was limited to analyzing all-cause GER of presumed infectious origin (not rotavirus-specific). Third, a potential cyclic pattern could be suspected with regards to the number of GER hospitalizations and
Figure 4. Number of gastroenteritis-related hospitalizations by age group, pre- and post-rotavirus vaccination in Panama. (Source: Hospital discharge data from database systematic review of five hospitals representing different settings in Panama (three urban hospitals: Hospital del Nino, Hospital de Especialidades Pediatricas, Hospital San Miguel Arcangel; one suburban: Hospital Nicolas Solano; and 1 rural: Hospital de Changuinola). Note: The mean baseline value is the mean number of gastroenteritis hospital discharges for baseline period 2000–2005. The numbers within the bars are the relative reductions in the observed numbers of hospital discharges during 2008 and 2009, as compared with baseline.).
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V. Bayard et al. / International Journal of Infectious Diseases 16 (2012) e94–e98
deaths reported in this study; however the numbers of GER deaths and hospitalizations reported during 2008 have been the lowest recorded in Panama. It is intended that the current study be continued for a minimum of 3 years in order to capture cyclical trends over time. In conclusion, the findings of our study demonstrate reductions in GER mortality and hospitalizations at only 2 years following the introduction of the rotavirus vaccine into the routine immunization schedule in Panama. A major impact was found in regions where vaccination coverage was higher, suggesting that maximizing vaccine coverage could lead to further reductions in GER mortality and hospitalizations. These data are the first evidence supporting the impact of vaccination among Panamanian children. Continued monitoring and disease surveillance networks are needed to further document the impact of rotavirus vaccination. Acknowledgements The authors thank the staff of the statistical records departments at the participating hospitals, Contralorı´a General de la Repu´blica (CGR), and the Expanded Program of Immunization of the Ministry of Health (Lic. Itzell Hewitt EPI Coordinator) for providing the data for this study; Mohammed Najeeb Ashraf for providing technical assistance with writing of the manuscript, Tatiana M. Lanzieri for critical review of the manuscript, Fla´via Rachel Moreira Lamara˜o and Jessica Mattos for publication coordination and editorial assistance on behalf of GlaxoSmithKline Biologicals; and GlaxoSmithKline Biologicals. We also thank the Panama team for contributing and supporting the coordination of the study and for monitoring activities. Funding source: This study was funded by GlaxoSmithKline Biologicals. Rotarix is a trademark of the GlaxoSmithKline group of companies. Rotateq is a trademark of the Merck group of companies, USA. Conflict of interest: All study investigators were funded though their institutions to carry out the study protocol. Maria Mercedes Castrejon, Rodrigo DeAntonio, Eduardo Ortega-Barria, and Romulo E. Colindres are employees of GlaxoSmithKline Biologicals. Eduardo Ortega-Barria and Romulo E. Colindres have stock ownership; Maria Mercedes Castrejon and Rodrigo DeAntonio have stock options. Vicente Bayard, Rodolfo Contreras, and Olga Tinajero declare no conflict of interest. References 1. Parashar UD, Gibson CJ, Bresee JS, Glass RI. Rotavirus and severe childhood diarrhoea. Emerg Infect Dis 2006;12:304–6.
2. World Health Organization. Rotavirus vaccines. Wkly Epidemiol Rec 2007;82:285–96. 3. Parashar UD, Burton A, Lanata C, Boschi-Pinto C, Shibuya K, Steele D, et al. Global mortality associated with rotavirus disease among children in 2004. J Infect Dis 2009;200:S9–15. 4. World Health Organization. Estimated rotavirus deaths for children under 5 years of age; Geneva: WHO; 2004. Available at: http://www.who.int/immunization_monitoring/burden/rotavirus_estimates/en/ (accessed April 25, 2011). 5. Parashar UD, Hummelmann EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003;9:565–72. 6. Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ 2003;81:197–204. 7. Centers for Disease Control and Prevention (CDC). Rotavirus surveillance— worldwide, 2001–2008. MMWR Morb Mortal Wkly Rep 2008;57:1255–7. 8. Rheingans RD, Constenla D, Antil L, Innis BL, Breuer T. Economic and health burden of rotavirus gastroenteritis for the 2003 birth cohort in eight Latin American and Caribbean countries. Rev Panam Salud Publica 2007;21:192–204. 9. World Health Organization. Meeting of the Immunization Strategic Advisory Group of Experts, April 2009—conclusions and recommendations. Wkly Epidemiol Rec 2009;84:220–36. 10. Danchin MH, Bines JE. Defeating rotavirus? The global recommendation for rotavirus vaccination. N Engl J Med 2009;61:919–21. 11. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006;354:11–22. 12. Vesikari T, Matson DO, Dennehy P, Damme PV, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human–bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23–33. 13. de Oliveira LH, Danovaro-Holiday MC, Andrus JK, de Fillipis AM, Gentsch J, Matus CR, et al. Sentinel hospital surveillance for rotavirus in Latin American and Caribbean countries. J Infect Dis 2009;200:S131–9. 14. de Oliveira LH, Danovaro-Holliday MC, Ruiz Matus C, Andrus JK. Rotavirus vaccine introduction in the Americas: progress and lessons learned. Expert Rev Vaccines 2008;7:345–53. 15. World Health Organization. Generic protocol for monitoring impact of rotavirus vaccination on rotavirus disease burden and viral strains. WHO/IVB/0816. Geneva: WHO; 2009, p. 1–73. 16. Patel MM, Tate JE, Selvarangan R, Daskalaki I, Jackson MA, Curns AT, et al. Routine laboratory testing data for surveillance of rotavirus hospitalizations to evaluate the impact of vaccination. Pediatr Infect Dis J 2007;26:914–9. 17. Ulm K. A simple method to calculate the confidence interval of a standardized mortality ratio. Am J Epidemiol 1990;131:373–5. 18. Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, Esparza-Aguilar M, Johnson B, Gomex-Altamirano CM, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. N Engl J Med 2010;362:299–305. 19. Linhares AC, Velazquez FR, Perez-Schael I, Saez-Llorens X, Abate H, Espinoza F, et al. Efficacy and safety of an oral live attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in Latin American infants: a randomised, double-blind, placebo-controlled phase III study. Lancet 2008;371:1181–9. 20. Lanzieri TM, Costa I, Shafi FA, Cunha MH, Ortega-Barria E, Linhares AC, et al. Trends in hospitalizations from all-cause gastroenteritis in children <5 years of age in Brazil before and after human rotavirus vaccine introduction, 1998-2007. Pediatr Infect Dis J 2010;29:673–5. 21. Sa´fadi MA, Berezin EN, Munford V, Almeida FJ, de Moraes JC, Pinheiro CF, et al. Hospital-based surveillance to evaluate the impact of rotavirus vaccination in Sa˜o Paulo, Brazil. Pediatr Infect Dis J 2010;29:1019–22. 22. Ministerio de Salud de Panama´. Memoria 2007:45-67. Available at: http:// www.minsa.gob.pa/minsa2008/final_newpage/documents/memorias/Salud%20Publica.pdf%20 (invalid%20encoding) (accessed April 25, 2011).
Contents lists available at SciVerse ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Impact of rotavirus vaccination on childhood gastroenteritis-related mortality and hospital discharges in Panama Vicente Bayard a,*, Rodrigo DeAntonio b, Rodolfo Contreras a, Olga Tinajero c, Maria Mercedes Castrejon b, Eduardo Ortega-Barrı´a d, Romulo E. Colindres d a
Instituto Conmemorativo Gorgas de Estudios de la Salud, Avenida Justo Arosemena Calle 35, APDO 0816-02593, Panama City, Panama GlaxoSmithKline Biologicals, Panama City, Panama Instituto de Investigaciones Cientı´ficas y Servicios de Alta Tecnologı´a (INDICASAT), Panama City, Panama d GlaxoSmithKline Biologicals, Rio de Janeiro, Brazil b c
A R T I C L E I N F O
S U M M A R Y
Article history: Received 21 July 2011 Accepted 6 September 2011
Background: Rotavirus vaccination was introduced in Panama in March 2006. This study was carried out in order to describe the trends in gastroenteritis-related (GER) hospitalizations and mortality in children <5 years of age during the pre- and post-vaccination periods. Methods: Data from the Expanded Program on Immunization (Ministry of Health) were used to calculate vaccine coverage. GER mortality and hospitalizations were obtained through database review of the Contralorı´a General de la Repu´blica and hospital discharge databases of five sentinel hospitals, for the period 2000–2008. Mean rates of GER mortality and mean numbers of hospitalizations during the baseline pre-vaccination period (2000-2005) were compared to those of 2007 and 2008. Results: National coverage for the second rotavirus vaccine dose increased from 30% in 2006 to 62% in 2007 and 71% in 2008, varying from 62% in the West region to 77% in the Panama region. Overall, at 2years post-vaccine introduction, the GER mortality rate in Panama had decreased by 50% (95% confidence interval (CI) 46–54). During 2000–2005, the GER mortality rate in children (<1 year) was 73/ 100 000, decreasing by 45% (95% CI 40–51) in 2008. In children aged 1–4 years, the GER mortality rate was 20.3/100 000 (2000–2005), decreasing by 54% (95% CI 48–60) in 2008. The Panama region registered the highest mortality rate reduction (69%; 95% CI 58–81) for 2008. During 2008, GER hospitalizations among children <5 years of age decreased by 30% (95% CI 21–37) from the mean number of hospitalizations during 2000–2005. Conclusions: A substantial reduction in GER mortality and hospitalizations was observed following the introduction of rotavirus vaccine in Panama. ß 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: William Cameron, Ottawa, Canada Keywords: Gastroenteritis Rotavirus vaccine Gastroenteritis-related deaths Gastroenteritis-related hospitalizations
1. Introduction Globally, rotavirus (RV) is the most common cause of acute diarrhea requiring hospitalization among infants and young children. Annually, rotavirus has caused over 611 000 deaths (range 454 000–705 000), approximately 2.4 million hospitalizations, and over 25 million clinic visits worldwide among children <5 years of age;1–3 more than 85% of these deaths occur in lowincome countries of Asia and Africa.4 The case fatality rate is often higher among children in low-income countries,5 though its incidence is similar in developed and developing countries.5,6 As per the World Health Organization (WHO) rotavirus surveillance network, approximately 40% (range 10–59%) of diarrhea hospita-
* Corresponding author. Tel.: +507 5274811; fax: +507 5274889. E-mail address: [email protected] (V. Bayard).
lizations among children <5 years of age worldwide, and 34% (range 10–51%) in the region of the Americas, were attributed to rotavirus infection prior to vaccine introduction.7 In Latin America, over 15 000 deaths, 75 000 hospitalizations, and 10 million cases of rotavirus diarrhea were reported annually.4 In Panama, prior to vaccine introduction, an estimated 15% of infants <6 months of age and 85% of infants <1 year old had had at least one episode of rotavirus infection.8 In order to reduce the global disease burden due to rotavirus gastroenteritis, effective and safe vaccines have been developed2,3,9,10 and are now recommended by the WHO for inclusion in national immunization programs.9 Two oral rotavirus vaccines are available in more than 100 countries worldwide: a two-dose TM human-attenuated rotavirus vaccine RIX4414 (Rotarix ; GlaxoSmithKline Biologicals, Rixensart, Belgium) and a three-dose live TM pentavalent bovine–human reassortant vaccine (Rotateq ; Merck, Whitehouse Station, NJ, USA). Both vaccines have demonstrated an
1201-9712/$36.00 – see front matter ß 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2011.09.003
V. Bayard et al. / International Journal of Infectious Diseases 16 (2012) e94–e98
established efficacy against severe rotavirus disease (85–98%) and against all-cause acute gastroenteritis (42–59%) in clinical trials.11,12 Based on these encouraging results, some of the countries of Latin America, including Brazil, Venezuela, El Salvador, and Mexico, have introduced rotavirus vaccines into their national programs (up until 2007).13 In March 2006, Panama introduced the human-attenuated rotavirus vaccine into its Expanded Program on Immunization (EPI) for the entire Panamanian birth cohort (70 000 children per year) using a two-dose scheme for children under 6 months.14 The WHO recommends that vaccine impact be assessed by monitoring trends in hospitalizations and mortality from all-cause acute gastroenteritis using secondary data sources.15 Following the introduction of rotavirus vaccines into immunization programs, global rotavirus surveillance networks were established to monitor the performance of the vaccines.13,16 The present study was undertaken to evaluate gastroenteritis-related (GER) hospitalizations and mortality trends in children <5 years of age before and after the introduction of rotavirus vaccination in Panama. 2. Methods Data on the number of rotavirus vaccine doses administered as first and second doses by region were obtained from the EPI of the Panamanian Ministry of Health. Vaccine coverage was calculated for the age group <1 year using the population estimated by the census as the denominator and stratified by region, as follows: (1) West region (Bocas del Toro, Chiriquı´, and Comarca Ngo¨be Bugle´), (2) Central region (Cocle´, Herrera, Los Santos, and Veraguas), (3) Panama region (East Panama, West Panama, Metropolitan Panama, and San Miguelito), and (4) Northeast region (Colo´n, Darie´n, and Comarca Kuna Yala). National mortality data for GER outcomes in children <5 years of age during 2000–2008 were obtained from the Contralorı´a General de la Repu´blica (CGR) databases. The Vital Statistics Department of CGR from Panama is responsible for data on main/ primary cause of death obtained from death certificates, and has an estimated coverage of >85% of all deaths reported in Panama. Mortality data are recorded at the municipality level, reported, reviewed, and entered into the province database, and transmitted electronically to the national level. Data from the CGR are the recognized official national mortality data. There are 13 main hospitals nationwide providing pediatric medical care (two tertiary care and 11 secondary care hospitals). We reviewed the databases of the main five hospitals representing different settings in Panama (three urban hospitals: Hospital del ˜ o, Hospital de Especialidades Pediatricas, Hospital San Miguel Nin Arcangel; one suburban: Hospital Nicolas Solano; and one rural: Hospital de Changuinola), which are considered as reference hospitals for pediatric care across the country. Both GER mortality and hospitalization data were collected using the International Classification of Diseases, 10th revision (ICD-10), including diarrhea and gastroenteritis of presumed infectious origin (A09X). Annual GER mortality rates were calculated using the population estimates from population data in the census as the denominator. The mean rate of GER mortality and number of hospitalizations during 2000–2005 was used as the baseline against which to compare the post-vaccination years (2007 and 2008). As rotavirus vaccine was introduced in Panama in early 2006, this year was considered a transitional year and excluded from the analysis. The absolute and relative reduction in deaths and mortality rates were computed with 95% confidence intervals (CI) using the exact Poisson confidence limit.17 Analysis was stratified according to age groups <1 year and 1–4 years and by region. All statistical analyses were performed using SAS v. 9.1, Epi Info v. 3.4.3, and Microsoft Excel.
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3. Results 3.1. Rotavirus vaccine coverage A total of 284 328 rotavirus vaccine doses, 60% as first doses and 40% as second doses, were administered between March 2006 and December 2008 to children aged <1 year in Panama. Vaccine coverage of the first dose in children <1 year of age was 62% in 2006, 89% in 2007, and 91% in 2008, while second dose coverage was 30%, 62%, and 71%, respectively. Vaccine coverage varied across regions. The Panama region had the highest two-dose coverage in the country, with 70% in 2007 and 77% in 2008, in comparison to the other regions, as shown in Figure 1. However, all regions showed an increase in vaccine coverage over time for both doses. 3.2. GER mortality From 2000 to 2008, 883 GER deaths were reported among children <5 years of age in Panama; 424 (48%) in children <1 year of age and 459 (52%) in children aged 1–4 years. The mean number of GER deaths in children <5 years of age during the prevaccination period of 2000–2005 was 103 (95% CI 92–112). Most of these cases occurred in the West region (60%). All regions reported a reduction in the number of GER deaths in children <5 years of age during 2008, with the highest reduction in the Panama region (66%; 95% CI 55–72) and the lowest reduction in the Northern region (33%; 95% CI 12–52) (Figure 2). Overall, the number of deaths in children <5 years of age was reduced by 47% (95% CI 41– 52). The absolute number of GER deaths in children aged <1 year and 1–4 years decreased from a mean of 49 and 54, respectively, during the pre-vaccination period, to 28 (43%; 95% CI 38–47) and 26 (51%; 95% CI 43–58), respectively, during 2008. Trends in the GER mortality rate are presented in Figure 3. The GER mortality rate in children under 5 years of age during 2000– 2005 was 31.1 per 100 000 children and decreased by 50% (95% CI 46–54) in 2008, with a rate of 15.5 per 100 000 children (Table 1). The highest mortality rate prior to vaccine introduction was observed in the West region, with a mean of 79.9 per 100 000 children, decreasing by 48% (95% CI 43–52) in 2008. The Panama region registered the highest reduction in mortality rate of 69% (95% CI 58–81) for 2008. In children <1 year of age, the GER mortality rate during 2000–2005 was 73 per 100 000 children, decreasing by 45% (95% CI 40–51) during 2008. In children 1–4 years of age, the GER mortality rate during 2000–2005 was 20.3 per 100 000 children, decreasing by 54% (95% CI 48–60) in 2008. 3.3. GER hospitalizations During 2000–2008, a total of 26 700 GER hospitalizations were observed in children <5 years of age at the five pediatric hospitals included in this study. During the pre-vaccination period (2000– 2005), 18 021 GER hospitalizations were observed in children <5 year of age, with a mean of 3004 hospitalizations per year (95% CI 2671–3336) during 2000–2005, decreasing by 4% (95% CI 8–13) and 30% (95% CI 21–37) in 2007 and 2008, respectively. Over 67% of GER hospitalizations in children <5 years of age were at the ˜ o during the pre-vaccination period, the main Hospital del Nin reference pediatric hospital in Panama, in which reductions of 36% (95% CI 10–50) in 2007 and 43% (95% CI 19–55) in 2008 were observed. Among children <1 year of age, 6372 GER hospitalizations were observed during 2000–2005, with a mean of 1062 (95% CI 913– 1210) hospitalizations per year, decreasing by 7% (95% CI 1–18) in 2007 and 28% (95% CI 4–17) in 2008. In children 1–4 years of age, 11 649 GER hospitalizations occurred during 2000–2005, with a
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Figure 1. Vaccine coverage (%) in children <1 year of age by vaccine dose and region, Panama, 2006–2008. (Source: Vaccination information from the Expanded Program on Immunization (EPI) of the Ministry of Health in Panama; population data provided by the Directorate of Statistics based on the population census of the CGR).
mean of 1942 per year (95% CI 1702–2180) and reductions of 2% (95% CI 11–13) in 2007 and 31% (95% CI 20–38) in 2008 (Figure 4).
4. Discussion The present study used secondary data sources to monitor trends in GER morbidity and mortality in children <5 years of age, before and after the introduction of the human-attenuated rotavirus vaccine into the EPI in Panama in March 2006. In 2008, just 2 years after national rotavirus vaccine introduction, a substantial reduction in the number of GER hospitalizations (30%) and deaths (47%) was observed, compared to the baseline prevaccination period. This decline was most pronounced in the Panama region where vaccine coverage was the highest, suggesting the likely impact of rotavirus vaccination. The number of children receiving the first dose of the rotavirus vaccine was more than the number receiving both doses in all regions in the study. Vaccine coverage for two doses during the first year following the introduction of the rotavirus vaccine in children aged <1 year (2006) was only 30%. Nevertheless, this coverage increased to 62%
in 2007 and 71% in 2008, leading to trends in reduction in the number of GER hospitalizations and deaths. A decrease in GER mortality rate by 45% (95% CI 40–51) was observed in children <1 year of age and by 54% (95% CI 48–60) in children 1–4 years of age during 2008, compared to the baseline pre-vaccination period. These findings are consistent with data from Mexico where a decline in the diarrhea-related mortality rate of 41% for children aged <1 year and 29% for those children aged 1– 2 years was observed after the introduction of the humanattenuated rotavirus vaccine.18A decreasing trend in GER mortality rates was observed in 2007 in the Central and Panama regions, 1 year after the introduction of the rotavirus vaccine. However, mortality rates did not show a significant reduction in the West and Northeast regions during 2007, probably because these regions are inhabited by large migrant indigenous communities with more limited access to medical care, poor sanitation, and low vaccine coverage, making them more susceptible to infectious diseases. A phase III clinical trial of the human-attenuated rotavirus vaccine in Latin America showed that all-cause GER hospitalizations were reduced by 39%,11,19 suggesting rotavirus vaccination
Figure 2. Number of gastroenteritis-related deaths among children aged <5 years pre- and post-rotavirus vaccination by region, Panama. (Source: Mortality data provided by CGR in Panama; population data provided by the Directorate of Statistics based on the population census of the CGR; vaccination information obtained from the Expanded Program on Immunization (EPI) of the Ministry of Health in Panama. Note: The mean baseline value is the mean number of GERD for the baseline period 2000–2005).
V. Bayard et al. / International Journal of Infectious Diseases 16 (2012) e94–e98
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Figure 3. Trends over-time for gastroenteritis-related mortality rate by age group in Panama (2000–2008). aChi-square test for linear trend p < 0.05; bChi-square test for linear trend p = 0.07. (Note: The gray line indicates when the human-attenuated rotavirus vaccine was introduced in 2006. Source: Mortality data provided by CGR in Panama; population data provided by the Directorate of Statistics based on the population census of the CGR.).
Table 1 Gastroenteritis-related mortality rate (per 100 000) in Panama (2007 and 2008) compared with baseline period (2000–2005), by age group Age group
<1 year 1–4 years Overall
Baseline pre-vaccination period (2000–2005)
2007
Mean mortality rate
Mortality rate
% Reduction (95% CI)
2008 Mortality rate
% Reduction (95% CI)
73 20.3 31.1
77 20.2 31.7
5 ( 7 to 4)a 0.5 ( 0.7 to 0.8)a 1.9 ( 1 to 3)a
40 9 15.5
45 (40 to 51)b 54 (48 to 60)b 50 (46 to 54)b
Source: Mortality data provided by CGR in Panama. Population data provided by the Directorate of Statistics based on the population census of the CGR. a p > 0.05. b p < 0.05.
plays a major role in reducing disease burden due to gastroenteritis. In Panama, the number of GER hospitalizations in 2008 decreased by 28% in children aged <1 year and 31% in those aged 1–4 years, compared to the pre-vaccination period. A recent study in Brazil has reported a reduction of approximately 48% in hospitalizations among children <1 year of age.20 The reduction in GER hospitalizations among children aged 1–4 years suggests a possible herd protection effect.9,21 The annual report of the Ministry of Health of Panama did not document any important changes with regards to interventions in
sanitation, hygiene, or nutrition during 2007 and 2008 compared to 2000–2005, thus it is likely that the decrease in GER outcomes is an effect of vaccine introduction.22 Nonetheless, several caveats must be considered when interpreting our findings. First, we had limited access to data due to the lack of electronic records for hospital discharges and also potential under-reporting of mortality data in some regions. Second, this was an ecological study that was limited to analyzing all-cause GER of presumed infectious origin (not rotavirus-specific). Third, a potential cyclic pattern could be suspected with regards to the number of GER hospitalizations and
Figure 4. Number of gastroenteritis-related hospitalizations by age group, pre- and post-rotavirus vaccination in Panama. (Source: Hospital discharge data from database systematic review of five hospitals representing different settings in Panama (three urban hospitals: Hospital del Nino, Hospital de Especialidades Pediatricas, Hospital San Miguel Arcangel; one suburban: Hospital Nicolas Solano; and 1 rural: Hospital de Changuinola). Note: The mean baseline value is the mean number of gastroenteritis hospital discharges for baseline period 2000–2005. The numbers within the bars are the relative reductions in the observed numbers of hospital discharges during 2008 and 2009, as compared with baseline.).
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deaths reported in this study; however the numbers of GER deaths and hospitalizations reported during 2008 have been the lowest recorded in Panama. It is intended that the current study be continued for a minimum of 3 years in order to capture cyclical trends over time. In conclusion, the findings of our study demonstrate reductions in GER mortality and hospitalizations at only 2 years following the introduction of the rotavirus vaccine into the routine immunization schedule in Panama. A major impact was found in regions where vaccination coverage was higher, suggesting that maximizing vaccine coverage could lead to further reductions in GER mortality and hospitalizations. These data are the first evidence supporting the impact of vaccination among Panamanian children. Continued monitoring and disease surveillance networks are needed to further document the impact of rotavirus vaccination. Acknowledgements The authors thank the staff of the statistical records departments at the participating hospitals, Contralorı´a General de la Repu´blica (CGR), and the Expanded Program of Immunization of the Ministry of Health (Lic. Itzell Hewitt EPI Coordinator) for providing the data for this study; Mohammed Najeeb Ashraf for providing technical assistance with writing of the manuscript, Tatiana M. Lanzieri for critical review of the manuscript, Fla´via Rachel Moreira Lamara˜o and Jessica Mattos for publication coordination and editorial assistance on behalf of GlaxoSmithKline Biologicals; and GlaxoSmithKline Biologicals. We also thank the Panama team for contributing and supporting the coordination of the study and for monitoring activities. Funding source: This study was funded by GlaxoSmithKline Biologicals. Rotarix is a trademark of the GlaxoSmithKline group of companies. Rotateq is a trademark of the Merck group of companies, USA. Conflict of interest: All study investigators were funded though their institutions to carry out the study protocol. Maria Mercedes Castrejon, Rodrigo DeAntonio, Eduardo Ortega-Barria, and Romulo E. Colindres are employees of GlaxoSmithKline Biologicals. Eduardo Ortega-Barria and Romulo E. Colindres have stock ownership; Maria Mercedes Castrejon and Rodrigo DeAntonio have stock options. Vicente Bayard, Rodolfo Contreras, and Olga Tinajero declare no conflict of interest. References 1. Parashar UD, Gibson CJ, Bresee JS, Glass RI. Rotavirus and severe childhood diarrhoea. Emerg Infect Dis 2006;12:304–6.
2. World Health Organization. Rotavirus vaccines. Wkly Epidemiol Rec 2007;82:285–96. 3. Parashar UD, Burton A, Lanata C, Boschi-Pinto C, Shibuya K, Steele D, et al. Global mortality associated with rotavirus disease among children in 2004. J Infect Dis 2009;200:S9–15. 4. World Health Organization. Estimated rotavirus deaths for children under 5 years of age; Geneva: WHO; 2004. Available at: http://www.who.int/immunization_monitoring/burden/rotavirus_estimates/en/ (accessed April 25, 2011). 5. Parashar UD, Hummelmann EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003;9:565–72. 6. Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ 2003;81:197–204. 7. Centers for Disease Control and Prevention (CDC). Rotavirus surveillance— worldwide, 2001–2008. MMWR Morb Mortal Wkly Rep 2008;57:1255–7. 8. Rheingans RD, Constenla D, Antil L, Innis BL, Breuer T. Economic and health burden of rotavirus gastroenteritis for the 2003 birth cohort in eight Latin American and Caribbean countries. Rev Panam Salud Publica 2007;21:192–204. 9. World Health Organization. Meeting of the Immunization Strategic Advisory Group of Experts, April 2009—conclusions and recommendations. Wkly Epidemiol Rec 2009;84:220–36. 10. Danchin MH, Bines JE. Defeating rotavirus? The global recommendation for rotavirus vaccination. N Engl J Med 2009;61:919–21. 11. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006;354:11–22. 12. Vesikari T, Matson DO, Dennehy P, Damme PV, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human–bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23–33. 13. de Oliveira LH, Danovaro-Holiday MC, Andrus JK, de Fillipis AM, Gentsch J, Matus CR, et al. Sentinel hospital surveillance for rotavirus in Latin American and Caribbean countries. J Infect Dis 2009;200:S131–9. 14. de Oliveira LH, Danovaro-Holliday MC, Ruiz Matus C, Andrus JK. Rotavirus vaccine introduction in the Americas: progress and lessons learned. Expert Rev Vaccines 2008;7:345–53. 15. World Health Organization. Generic protocol for monitoring impact of rotavirus vaccination on rotavirus disease burden and viral strains. WHO/IVB/0816. Geneva: WHO; 2009, p. 1–73. 16. Patel MM, Tate JE, Selvarangan R, Daskalaki I, Jackson MA, Curns AT, et al. Routine laboratory testing data for surveillance of rotavirus hospitalizations to evaluate the impact of vaccination. Pediatr Infect Dis J 2007;26:914–9. 17. Ulm K. A simple method to calculate the confidence interval of a standardized mortality ratio. Am J Epidemiol 1990;131:373–5. 18. Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, Esparza-Aguilar M, Johnson B, Gomex-Altamirano CM, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. N Engl J Med 2010;362:299–305. 19. Linhares AC, Velazquez FR, Perez-Schael I, Saez-Llorens X, Abate H, Espinoza F, et al. Efficacy and safety of an oral live attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in Latin American infants: a randomised, double-blind, placebo-controlled phase III study. Lancet 2008;371:1181–9. 20. Lanzieri TM, Costa I, Shafi FA, Cunha MH, Ortega-Barria E, Linhares AC, et al. Trends in hospitalizations from all-cause gastroenteritis in children <5 years of age in Brazil before and after human rotavirus vaccine introduction, 1998-2007. Pediatr Infect Dis J 2010;29:673–5. 21. Sa´fadi MA, Berezin EN, Munford V, Almeida FJ, de Moraes JC, Pinheiro CF, et al. Hospital-based surveillance to evaluate the impact of rotavirus vaccination in Sa˜o Paulo, Brazil. Pediatr Infect Dis J 2010;29:1019–22. 22. Ministerio de Salud de Panama´. Memoria 2007:45-67. Available at: http:// www.minsa.gob.pa/minsa2008/final_newpage/documents/memorias/Salud%20Publica.pdf%20 (invalid%20encoding) (accessed April 25, 2011).