SUPPLEMENT

Reduction of Diarrhea-associated Hospitalizations Among Children Aged 5 Years in Panama Following the Introduction of Rotavirus Vaccine
Yadira Molto, MD,* Jennifer E. Cortes, MD, Lucia Helena De Oliveira, RN, MSc, Adrianna Mike, RN,* Itzel Solis, RN,* Onix Suman, RN, Luis Coronado, MD, Manish M. Patel, MSc, MD, Umesh D. Parashar, MB BS, MPH, and Margaret M. Cortese, MD
In Latin America and the Carribean, Rotavirus is estimated to cause approximately 40% of all diarrhea-associated hospitalizations and deaths in children, and a quarter of ambulatory visits for diarrhea in children, resulting in approximately 2 million outpatient visits, 190,000 hospitalizations, and 5,000 deaths annually.2,3 In March 2006, Panama became one of the rst countries to introduce rotavirus vaccine into its national immunization program. Little baseline information about diarrhea disease burden in Panama is available, and there have been few studies on the effect of rotavirus vaccine since introduction.4 We examined data on rotavirus vaccine coverage and diarrhea-associated hospitalizations before and after vaccine introduction to assess the effect of vaccine on diarrhea epidemiology in Panama.

Background: In March 2006, rotavirus vaccine (Rotarix, RV1) was introduced into the Panamanian national immunization program. We assessed the effect of vaccine on diarrhea-associated hospitalizations among young Panamanian children. Methods: We obtained monthly numbers of diarrhea-associated hospitalizations among children aged 5 years during 2003 and 2008 from 5 health regions in Panama, representing 53% of the birth cohort. We compared the number of diarrhea-associated hospitalizations during the postvaccine years of 2007 and 2008 with the prevaccine mean numbers 20032005 among children 1 year and those 1 to 4 years of age. Administrative data were used to estimate national rotavirus vaccine coverage. Results: During prevaccine years, diarrhea-associated hospitalizations among children 5 years in the 5 regions averaged 4057 annually. After the vaccine introduction, a decrease in diarrhea-associated hospitalizations of 22% (898 fewer) occurred in 2007 and 37% (1502 fewer) in 2008. Greater reductions were observed during January through June, the months presumed to have high rotavirus activity in prevaccine years (33% reduction in 2007 and 58% in 2008, compared with prevaccine mean). Reduction estimates were similar among infants and those aged 1 4 years of age, even though only 25% of the latter group was likely to have received vaccine by early 2008. Estimated coverage with 1 dose of rotavirus vaccine among infants increased from 63% at the end of 2006 to 94% at the end of 2008. Conclusions: RV1 appears to have had a substantial impact on diarrheaassociated hospitalizations among young children in Panama. Key Words: rotavirus, vaccines, diarrhea, hospitalizations, Panama, children (Pediatr Infect Dis J 2011;30: S16 S20)

METHODS Setting and Study Design

Panama is an upper-middle income Latin American country with an annual birth cohort of approximately 70,000. Healthcare is provided through the public (Ministry of Health and Social Security Fund) and private sectors. Panama maintains national surveillance for diarrhea as it is one of the leading causes of morbidity in children. Hospital admissions and ambulatory visits for diarrhea are aggregated at the regional level and submitted monthly to the Ministry of Health, which maintains the national data. Vaccines for children aged 5 years are provided to all Panamanian children at no cost. The monovalent rotavirus vaccine (RV1) was added to the national vaccination program in March 2006, with doses recommended at ages 2 and 4 months, and a maximum age of 24 weeks for the second dose.

Data Collection and Analysis

otavirus is the leading cause of severe childhood diarrhea worldwide, resulting in approximately 2 million hospitalizations and more than 600,000 deaths in children 5 years of age.1,2

Accepted for publication September 28, 2010. From the *Ministry of Health, Panama City, Panama; National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA; Epidemic Intelligence Service, Ofce of Workforce and Career Development, Centers for Disease Control and Prevention, Atlanta, GA; Pan American Health Organization, Washington, DC; and El Hospital del Nino, Panama City, Panama. The ndings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC). Address for correspondence: Margaret M. Cortese, MD, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, NE, MS A47, Atlanta, GA 30333. E-mail: mcortese@cdc.gov. Copyright 2010 by Lippincott Williams & Wilkins ISSN: 0891-3668/11/3001-0016 DOI: 10.1097/INF.0b013e3181fefc68

We estimated 1- and 2-dose national RV1 coverage for 2006 2008 as the total number of rst and second doses actually administered to children, on the basis of the data from the Panama Expanded Program for Immunizations, divided by the number of live births for that calendar year. We assumed that all doses were given to infants in accordance with the age recommendations. In a similar manner, we estimated 1- and 2-dose pentavalent vaccine (DTP-HepB-Hib) coverage, which has a recommended administration scheduled at the same ages as rotavirus vaccine (at ages 2 and 4 months) for doses 1 and 2 and which had stable uptake during the study period. To evaluate the effect of rotavirus vaccine on diarrheaassociated hospitalizations, our goal was to obtain the monthly number of diarrhea-associated hospitalizations for children aged 5 years on the basis of available age groups (1 year and 1 4 years) during 20032008 from each of the 14 health regions. We dened a diarrhea-associated hospitalization as any hospitalization with an ICD-10 code for diarrhea (bacterial A00.0-A05.9, parasitic A06.0-A07.9, viral A08.0-A08.5, and

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presumed infectious diarrhea A09) or one collected as part of the required national diarrhea surveillance at a regional level. There was no overlap between denitions as reporting hospitals or regions used either the ICD-10 code or national surveillance data, but not both. Data from regions that contributed information for each year during 20032008 and that averaged at least 50 diarrhea-associated hospitalizations annually during prevaccine years were used in the study. Six hospitals representing 5 (Bocas del Toro, Chiriqu, Los Santos, Metropolitan region, and San Miguelito) of the 14 health regions in Panama met these criteria. These regions when combined include approximately 53% of the annual national birth cohort, with Metropolitan region representing 17%; San Miguelito, 16%; Chiriqui, 12%; Bocas del Toro, 6%; and Los Santos, 2%. Of the total diarrheaassociated hospitalizations at the 6 hospitals, 60% occurred in the Metropolitan region. Two pediatric referral hospitals, el Hospital del Nin o and el Hospital de Especialdades Pediatricas, are located in the metropolitan region. The larger of the two, the Hospital del Nin o, contributed 65% of the data for the region and 45% of the overall data. We used the data from these regions to examine trends of diarrhea-associated hospitalizations on the basis of month, year, and age group. We also obtained total number of hospitalizations

by month and year for children aged 5 years and subtracted the number of diarrheal hospitalizations from the total to obtain the number of nondiarrheal hospitalizations. We compared monthly trends in the number of diarrheaassociated hospitalizations during the postvaccine years of 2007 and 2008 with the prevaccine mean number of diarrhea-associated hospitalizations from the years 20032005. Data from the transitional year 2006 were excluded from calculations as vaccine was introduced during that year. We calculated the percent reduction of diarrheaassociated hospitalizations in 2007 and 2008 from the baseline mean by age group annually (January through December) and during the rst half of the year (January through June) when the incidence of rotavirus disease is expected to be high on the basis of seasonality data from nearby countries5 8 and the prevaccine data (monthly counts of diarrhea-associated hospitalizations exceeding the mean). To further examine trends, we also assessed the ratio of the annual number of diarrhea-associated hospitalizations per annual number of nondiarrheal hospitalizations for each region during the pre- and postvaccine periods, to help account for any changes in general hospitalization practices or catchment areas.

RESULTS
Estimated RV1 coverage increased rapidly after vaccine introduction in 2006. Coverage with 1 dose of RV1 was 66% at the end of 2006 and increased to 93% by the end of 2007, which was similar to the pentavalent (DTP-HepB-Hib) 1-dose coverage of 94%, and remained stable in 2008 (Table 1). Two-dose RV1 coverage was lower than 1-dose coverage, increasing from 32% at the end of 2006 to 72% by the end of 2008, but still lagging behind the 91% coverage with 2 doses of pentavalent vaccine. During the study period, 21,771 diarrhea-associated hospitalizations and 123,323 nondiarrheal hospitalizations for children aged 5 years were recorded. Before the introduction of RV1, diarrhea-associated hospitalizations among Panamanian children peaked (ie, exceeded the monthly mean for each year) during the rst half of the year (Fig. 1). A similar pattern was observed in 2006. Diarrhea-associated hospitalizations during

TABLE 1. Rotavirus and Pentavalent (DTP-HepBHib) Vaccine Coverage Among Children 1 Year of AgePanama, 2006 2008*
Vaccine Coverage, % Year Rotavirus 2006 2007 2008 66 93 94 Dose 1 Pentavalent 95 94 97 Rotavirus 32 65 72 Dose 2 Pentavalent 86 89 91

*Vaccine coverage was calculated from administrative data as the number of doses of vaccine administered during the year divided by the number of live births per year.

FIGURE 1. Monthly number of diarrhea-associated hospitalizations by year among children 5 years of agePanama, 20032008. Contributing regions include Metropolitan Region, Chiriqui, Bocas del Toro, San Miguelito, and Los Santos. The number of diarrhea-associated hospitalizations from the Hospital de Especialdades Pediatricas (1 of 2 hospitals contributing data from the Metropolitan region) was not available for the month of January 2003 and was estimated as the mean number of admissions during the month of January 2004 2006. 2010 Lippincott Williams & Wilkins
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FIGURE 2. Monthly number of diarrhea-associated hospitalizations after RV1 introduction compared with the monthly prevaccine mean and range among children 5 years of agePanama, 20032008. Contributing regions include Metropolitan Region, Chiriqui, Bocas del Toro, San Miguelito, and Los Santos. The number of diarrhea-associated hospitalizations from the Hospital de Especialdades Pediatricas (1 of 2 hospitals contributing data from the Metropolitan region) was not available for the month of January 2003 and was estimated as the mean number of admissions during the month of January 2004 2006. TABLE 2. Number of Diarrhea-associated Hospitalizations and Percent Reduction Before and After Rotavirus Vaccine Introduction, by Age Group
2007 Age Group 20032005 Mean (Range) n % Reduction 22 15 26 33 37 32 n 2008 % Reduction 37 31 40 58 55 59

Annual All 5 yr 1 yr 1 4 yr JanuaryJune All 5 yr 1 yr 1 4 yr

4057 (3260 5059) 1359 (1090 1633) 2698 (2170 3425) 2406 (17123263) 776 (5421041) 1630 (1170 2221)

3159 1155 2004 1604 491 1113

2555 941 1614 1013 352 661

Contributing regions include Metropolitan Region, Chiriqui, Bocas del Toro, San Miguelito, and Los Santos. The number of diarrhea-associated hospitalizations from the Hospital de Especialdades Pediatricas (1 of 2 hospitals contributing data from the Metropolitan region) was not available for the month of January 2003 and was estimated as the mean number of admissions during the month of January 2004 2006.

the rst half of the year decreased in 2004 and 2005, but subsequently increased in 2006, consistent with secular variation. In 2007, the peak for diarrhea-associated hospitalizations occurred later in the year, between April and August. In 2008, the seasonality of diarrhea hospitalizations was less well-dened with peak number occurring in September. During October 2006 through March 2007, and during October 2007 through June 2008, the numbers of diarrhea-associated hospitalizations among children aged 5 years were less than the lowest of the prevaccine years (Fig. 2). Diarrhea-associated hospitalizations among children aged 5 years averaged 4057 per year before the introduction of RV1 (Table 2). Compared with this prevaccine average, a decrease in hospitalizations of 22% (898 fewer hospitalizations) occurred in 2007 and 37% (1502 fewer) in 2008. The number of diarrhea-associated hospitalizations in 2008 was lower than that in the lowest prevaccine year for which data were available (2005) in both age groups. Greater reductions were observed during the rst half of each year (33% reduction in 2007 and

58% in 2008, compared with prevaccine mean) and were similar among infants and those 1 4 years of age (Table 2). In 2007 and 2008, The number of diarrhea-associated hospitalizations during January through June was also lower as compared with the lowest prevaccine year available for both age groups. When data on number of diarrhea-associated hospitalizations for children 5 years of age were examined by region, annual reductions occurred in 3 of 5 regions in 2007 and 4 of 5 in 2008 (Table 3). In the 3 regions with the lower number of prevaccine hospitalizations (Bocas del Toro, Los Santos, and San Miguelito), the annual number of diarrhea-associated hospitalizations increased in 2007 compared with prevaccine mean, but only the region with the lowest prevaccine number, Los Santos, also had an increase in 2008. In the January through June assessment, 4 of the 5 regions had a reduction in 2007 and all 5 had a reduction in 2008 (range, 19%74%) (Table 3). Reductions were greatest during January through June, 2008, in the 2 regions with the greatest number of prevaccine hospitalizations: Chiriqui experienced a 74% reduction and the Metropolitan region had a decline of 59%. 2010 Lippincott Williams & Wilkins

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TABLE 3. Annual and January through June Number of Diarrhea-associated Hospitalizations and Percent Reduction Among Children 5 Years of Age, by Health Region, Panama, 2007 and 2008
Annual Region Prevaccine Mean* 2007 All regions Metropolitan region Hospital del Nio Esp Pediatricas Chiriqui Bocas del Toro San Miguelito Los Santos 4057 2401 1747 654 841 424 316 76 3159 1766 1402 364 393 453 451 96 2008 2555 1604 1244 360 285 342 227 97 2007 22 26 20 44 53 7 43 26 2008 37 33 29 45 66 20 28 27 2406 1381 1024 357 565 253 159 47 n % Reduction Prevaccine Mean* 2007 1604 973 801 172 177 210 215 29 2008 1013 561 444 117 147 173 94 38 2007 33 30 22 52 69 17 36 38 2008 58 59 57 67 74 32 41 19 JanuaryJune n % Reduction

*Prevaccine mean calculated as the average of the number of diarrhea-associated hospitalizations during 20032005 annually and January through June. The number of diarrhea-associated hospitalizations from the Hospital de Especialdades Pediatricas (1 of 2 hospitals contributing data from the Metropolitan region) was not available for the month of January 2003 and was estimated as the mean number of admissions during the month of January 2004 2006.

During this time of reduction in diarrhea-associated hospitalizations, an increase in total number of annual nondiarrheal hospitalizations occurred. Annual nondiarrheal hospitalizations averaged 19,380 (range, 18,63120,703) during prevaccine years and increased 2% (n 20,285) in 2007 and 15% (n 22,715) in 2008. However, some individual regions experienced a decrease in nondiarrheal hospitalizations in 2007 and 2008. When the ratio of the annual number of diarrhea-associated hospitalizations to nondiarrheal hospitalizations in 2007 was compared with the prevaccine mean for each region, only San Miguelito demonstrated a notable increase (having had an increase in diarrhea-associated hospitalizations with a decrease in nondiarrheal hospitalizations); Bocas del Tora demonstrated a 1% increase, whereas Los Santos showed a reduction (32%). In 2008, compared with the prevaccine mean, all regions demonstrated a reduction in the ratio of diarrhea-associated hospitalizations to nondiarrheal hospitalizations, including San Miguelito (25%), Bocas del Tora (28%), and Los Santos (36%). Chiriqui and the Metropolitan region demonstrated a reduction in this ratio in 2007 and 2008 that was within 3 percentage points of the reduction estimate using absolute counts of diarrhea hospitalizations (data not shown).

DISCUSSION
RV1 appears to have had a substantial impact on diarrhea-associated hospitalizations among young Panamanian children. Although rotavirus-specic data with laboratory conrmation were not available, the data examined support that the burden of severe rotavirus disease has declined in Panama after the introduction of rotavirus vaccine. Reductions were greater in the second year (2008), with an additional cohort of vaccinated children. Furthermore, reductions were greater in the January to June period, the period encompassing months with high rotavirus activity in nearby countries5 8 and the period when diarrhea hospitalizations were most common in the prevaccine years. These reductions in diarrhea-associated hospitalizations during the postvaccine period coincided with an overall modest increase in nondiarrheal hospitalizations. We have no reason to believe that the latter nding was a result of rotavirus vaccine introduction. Therefore, if the reductions in diarrhea-associated hospitalizations from the regions analyzed are representative of the other regions in Panama, rotavirus vaccine may have prevented an additional 6% of total hospitalizations from occurring in 2008 among children aged 5 years. 2010 Lippincott Williams & Wilkins

Reductions of diarrhea-associated hospitalizations were prominent across both age groups, even though approximately 75% of children in the older age group (1 4 years) never had the opportunity to receive the vaccine, as they were already above the rst-dose age limit when RV1 was introduced in 2006. The reduction in diarrhea hospitalizations of approximately 58% in the January through June 2008 period for children 1 through 4 years of age could indicate that the younger children in the age group (with high rotavirus vaccine coverage overall per administrative data) contributed most of the rotavirus burden prevaccine and directly protecting these children alone resulted in the large reduction in hospitalizations. It is also possible that older children in the 1 through 4-year age group who would not have directly received vaccine may have experienced reductions in diarrhea burden as possible indirect benets of rotavirus vaccine. This has been observed in other countries after rotavirus vaccine introduction.9 12 Collecting data for each 1-year cohort in Panama would be valuable. Particularly for the smaller regions, some regional variation was observed in the level of reduction for diarrhea-associated hospitalizations. This could be related to secular trends of rotavirus disease within the country, local differences in the burden of other diarrhea pathogens during these years, regional differences in hospitalization practices and healthcare seeking behaviors, or differences in vaccine coverage. There are several limitations to this study. First, not all regions of the country contributed data; however, the regions that experience the highest numbers of pediatric hospitalizations (Metropolitan region and Chiriqui) were represented. Second, we evaluated all diarrhea-associated hospitalizations, but could not assess rotavirus-specic hospitalizations as rotavirus testing was not performed. Therefore, we could neither assess whether there was a postvaccine delay in the onset of the rotavirus season in addition to disease reduction (as seen in the United States)10 12 nor the etiology of the diarrhea cases observed in mid 2007. Third, these data are not populationbased, as the catchment areas for the hospitals were unknown. To help address this, we examined the change in ratio of diarrhea-associated hospitalizations to nondiarrheal hospitalizations for each region, and the reductions observed support the conclusion that the burden of severe diarrhea illness decreased after vaccine introduction. Finally, due to the ecological nature of the study, we could not be certain that reductions in diarrhea-associated hospitalizations were solely because of vaccine effect.
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In conclusion, diarrhea-associated hospitalizations among Panamanian children aged 5 years have decreased substantially in 2 consecutive seasons after the introduction of rotavirus vaccine in 2006. Further studies on vaccine effectiveness and healthcare utilization for rotavirus-specic diarrhea will be useful to fully assess the impact of rotavirus vaccine in Panama.

ACKNOWLEDGMENTS
We thank Drs. Gregory Armstrong and Susan Goldstein for their careful review of the manuscript and the regional epidemiology staff in Panama for providing the data. REFERENCES
1. Parashar UD, Hummelman EG, Bresee JS, et al. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis. 2003;9:565572. 2. Parashar UD, Gibson CJ, Bresee JS, et al. Rotavirus and severe childhood diarrhea. Emerg Infect Dis. 2006;12:304 306. 3. Rheingans RD, Constenla D, Antil L, et al. Economic and health burden of rotavirus gastroenteritis for the 2003 birth cohort in eight Latin American and Caribbean countries. Rev Panam Salud Publica. 2007; 21:192204. , Gonza 4. Nieto Guevara J, Lo pez O lez G. Impacto de la introduccio n de la vacuna contra el rotavirus en la hospitalizacio n por gastroenteritis aguda grave en el Hospital del Nin o de la Ciudad de Panama in Portuguese. Rev Panam Salud Publica. 2008;24:189 194.

5. Amador JJ, Vasquez J, Orozco M, et al. Rotavirus disease burden, Nicaragua 20012005: dening the potential impact of a rotavirus vaccination program. Int J Infect Dis. 2010;14:e592 e595. 6. Solo rzano Giro n JO, Molina IB, Turcios-Ruiz RM, et al. Burden of diarrhea among children in Honduras, 2000 2004: estimates of the role of rotavirus. Rev Panam Salud Publica. 2006;20:377384. 7. Armero Guardado JA, Clara AW, Turcios RM, et al. Rotavirus in El Salvador: an outbreak, surveillance and estimates of disease burden, 20002002. Pediatr Infect Dis J. 2004;23(suppl 10):S156 S160. 8. Kane EM, Turcios RM, Arvay ML, et al. The epidemiology of rotavirus diarrhea in Latin America. Anticipating rotavirus vaccines. Rev Panam Salud Publica. 2004;16:371377. 9. Lambert SB, Faux CE, Hall L, et al. Early evidence for direct and indirect effects of the infant rotavirus vaccine program in Queensland. Med J Aust. 2009;191:157160. 10. Cortese MM, Tate JE, Simonsen L, et al. Reduction in gastroenteritis in United States children and correlation with early rotavirus vaccine uptake from national medical claims databases. Pediatr Infect Dis J. 2010;29:489 494. 11. Curns AT, Steiner CA, Barrett M, et al. Reductions in acute gastroenteritis hospitalizations among US children after introduction of rotavirus vaccine: analysis of hospital discharge data from 18 US states. J Infect Dis. 2010;201:16171624. 12. Tate JE, Panozzo CA, Payne DC, et al. Decline and change in seasonality of US rotavirus activity after the introduction of rotavirus vaccine. Pediatrics. 2009;123:465 471.

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