Vaccine 33 (2015) 222–227
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Impact of a combined pediatric and adult pneumococcal immunization program on adult pneumonia incidence and mortality in Nicaragua ˜ e, Sylvia Becker-Dreps a,∗ , Erick Amaya b , Lan Liu c , Julio Rocha d , Rafaela Briceno e d c ´ , Michael G. Hudgens , Christopher W. Woods f , Gilberto Moreno , Jorge Aleman David J. Weber a a
University of North Carolina School of Medicine, Chapel Hill, NC, USA National Autonomous University of Nicaragua, León, Nicaragua c UNC Gillings School of Global Public Health, Chapel Hill, NC, USA d Hospital Escuela Oscar Danilo Rosales Argüello (HEODRA), León, Nicaragua e Sistemas Locales de Atención Integral a la Salud, León (SILAIS-León), León, Nicaragua f Duke University School of Medicine, Durham, NC, USA b
a r t i c l e
i n f o
Article history: Received 1 April 2014 Received in revised form 20 September 2014 Accepted 6 October 2014 Available online 4 November 2014 Keywords: Adults Nicaragua Pneumonia Pneumococcal vaccine Streptococcus pneumoniae.
a b s t r a c t Background: In 2010, Nicaragua implemented an adult immunization program with the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and a pediatric immunization program with the 13-valent pneumococcal conjugate vaccine (PCV-13). We assessed incidence rates of ambulatory visits and hospitalizations for pneumonia and pneumonia-related mortality in adults over the age of 50 years before and after the program’s implementation in the Department of León, Nicaragua. Methods: We collected visit diagnoses from all 107 public health facilities between 2008 and 2012 in León. We compared incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, and pneumonia-related mortality in the pre-vaccine (2008–2009) and vaccine (2011–2012) periods among older adults using Poisson regression with generalized estimating equations (GEE), controlling for age group, municipality, and proportions of adults who were immunized against influenza. Exposure time was estimated by official municipality population estimates. Results: We did not observe lower incidence rates of ambulatory visits or hospitalizations for pneumonia among adults during the vaccine period versus the pre-vaccine period. However, pneumonia-related mortality was lower in the vaccine period versus the pre-vaccine period, with an adjusted incidence rate ratio (IRRa) of 0.73 (0.56, 0.94) among adults aged 50–64 years, and 0.55 (0.43, 0.70) among adults aged ≥65 years. Conclusions: These early results following introduction of a combined pediatric and adult pneumococcal immunization program in Nicaragua show a probable impact of the program on the reduction of pneumonia-related deaths in older adults, but a less clear impact on the reduction of health facility visits for pneumonia. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Streptococcus pneumoniae remains a major cause of morbidity and mortality at both young and old extremes of life [1–4]. Among
∗ Corresponding author at: Department of Family Medicine, UNC School of Medicine, 590 Manning Drive, Chapel Hill, NC 27599-7595, USA. Tel.: +1 919 966 3711; fax: +1 919 966 6125. E-mail address: [email protected] (S. Becker-Dreps). http://dx.doi.org/10.1016/j.vaccine.2014.10.073 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
older adults in Latin America, community-acquired pneumonia is the third most common cause of mortality, and S. pneumoniae is the most frequently identified cause of pneumonia [5]. Without intervention, the burden of pneumococcal disease will increase as the Latin American population ages over coming decades, due to increased susceptibility to infection and higher risk of severe disease and complications from infection in this age group [6–9]. To reduce the burden of pneumococcal disease in children, many high-income countries (HICs) have implemented routine pediatric immunization with pneumococcal conjugate vaccines (PCVs).
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These pediatric PCV immunization programs have reduced the burden of pneumococcal disease among children [10–15], but have also lowered the incidence of pneumonia and pneumococcal colonization by vaccine serotypes in adults [16–18]. In light of this evidence of herd protection of adults, and also due to the incomplete protective effect of the pneumococcal polysaccharide vaccine (PPSV-23) in target groups [19,20], the WHO currently recommends the prioritization of pediatric PCV immunization programs in resource-limited settings [21,22]. The Nicaraguan Ministry of Health began a pediatric pneumococcal immunization program with the 13-valent pneumococcal conjugate vaccine (PCV-13, intramuscular, Pfizer) in December 2010 with a “3 + 0” dosing schedule, adding to the existing National Immunization Schedule [23]. Earlier the same year, due to a vaccine donation, the Ministry of Health also began offering a single dose of PPSV-23 (Merck, intramuscular) to adults aged 50 years and older. For both of these age groups, the pre-vaccine burden of pneumococcal disease and distribution of circulating pneumococcal serotypes is largely unknown in Nicaragua, as in many other low-middle income countries (LMICs). Also, individuals in LMICs may have differences in the immune response to vaccines as compared to HIC individuals, as has been observed with certain oral vaccines [24,25]. A prior study examined the impact of Nicaragua’s pneumococcal immunization program on children and found an estimated 30% reduction in hospitalizations due to pneumonia among age groups eligible to receive PCV-13 [26]. The goal of this study was to examine the overall effect [27] of the combined child and adult pneumococcal immunization program: the change in the incidence rate of health facility visits and deaths due to pneumonia in older adults before and after the program’s implementation.
2. Methods 2.1. Setting This ecological study was conducted in the Department of León in western Nicaragua. Nicaragua is an LMIC in Central America with a per capita GNI of $1650 [28]. Despite its low per capita GNI, Nicaragua has a well-functioning National Immunization Program, with adequate cold storage capacity [29]. Beginning in 2007, new federal legislation increased the population’s accessibility to public facilities by removing costs associated with clinic visits and hospitalizations. The Department of León, where the study was conducted, includes the country’s second largest city, León (2012 estimated city population: 193,598), five peri-urban municipalities, and four rural municipalities (2012 estimated department population: 396,969).
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facilities was de-identified, analysis of this data was determined to be exempt from full IRB review. 2.3. Assignment of diagnosis codes and information management The diagnoses of interest to this study include pneumonia and death due to pneumonia. Hospital diagnosis codes are assigned at the time of admission by the medical team admitting the patient and are maintained by the hospital epidemiology office in an electronic database. Similarly, emergency department visit codes are assigned by the medical team treating the patient in the emergency department. The definition of pneumonia used by hospital physicians is defined on page 72 of the Ministry of Health’s Management Protocol of Common Medical Problems in Adults [30], as an infectious syndrome including respiratory and constitutional symptoms, present with physical exam findings of consolidation, with confirmation of infiltrates on a chest radiograph. According to the Management Protocol and HEODRA protocols, all patients admitted for pneumonia are required to receive a chest radiograph. If a patient admitted with the diagnosis of pneumonia dies from pneumonia during the hospitalization or if a patient arrives to the HEODRA emergency department and dies prior to admission, a report of hospital death due to pneumonia is recorded. The database includes the date of admission, gender, age group, and municipality of origin. Data are entered into the electronic database within 1 week of presenting to the hospital. Ambulatory visit diagnosis codes are assigned by the health care provider caring for the patient and are maintained in an electronic database at the epidemiology office of the local health ministry, or, Sistemas Locales de Atención Integral a la Salud-León (SILAISLeón). The definition of pneumonia used by the ambulatory primary care providers includes the same clinical signs and symptoms as described above, but typically does not include chest radiography, as this is not available in the majority of settings. Deaths occurring outside the hospital are investigated by a team including a physician from SILAIS-León, the local physician, and an epidemiologist. If the team determines that the cause of death is pneumonia, a report of death due to pneumonia is entered into the electronic database. The database includes information on the date of the visit or report, gender, age group, and municipality of origin. 2.4. Population estimates The national census is performed every 10 years by the Nicaraguan Institute of Development Information (INIDE), with the last census occurring in 2005. Official population estimates by age group for each municipality are provided for intervening years by SILAIS-León. 2.5. Vaccine coverage by municipality
2.2. Health facilities Hospital data were collected at the single public referral hospital in the department of León, Hospital Escuela Oscar Danilo Rosales ¨ Arguello (HEODRA). During the years studied (2008–2012), the numbers of all-cause hospitalizations at HEODRA remained relatively stable with a low of 21,627 in 2008 and a high of 23,155 in 2010. Ambulatory visit data were collected from the 106 public primary care facilities (primary care centers and health posts) in the department in addition to the emergency department of HEODRA. Both public primary care facilities and public hospitals are under a government mandate to report visits for pneumonia to their departmental epidemiology office. The local health ministry estimates that 10% of the population access private health facilities instead of public health facilities. As data obtained from health
The National Immunization Program maintains data on immunization coverage by year and age group for each routinely administered vaccine. The PPSV-23 adult immunization program began in May 2010. The proportion of the adult population who were immunized with PPSV-23 by municipality and year are shown in Table 1. At the end of the first year of the PPSV-23 immunization program (2010), coverage with PPSV-23 among adults over age 50 varied between 25 and 29% by municipality. If we assume that the population was stable, coverage with PPSV-23 by the end of 2012 would be approximately 50%. The PCV-13 pediatric immunization program began in December 2010. By the end of 2011, 63% of infants in the department of León had received three doses of PCV-13, with coverage ranging between 49 and 71% by municipality. By the end of 2012, 97% of infants in the department had received three
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Table 1 Proportion of population (%) immunized each year by municipality. Municipality
Adults over age 50 years
Infants
PPSV-23a
Achuapa El Sauce Santa Rosa Jicaral Larreynega Telica Quezalguaque León La Paz Centro Nagarote All Municipalities a b c d
PCV-13d
Influenza
2010
2011
2012
2008b
2009
2010c
2011
2012
2011
2012
27 27 27 28 29 27 27 26 27 25 27
18 13 18 18 13 22 13 12 21 17 15
12 14 15 12 15 12 13 9 12 10 11
9 8 14 13 25 3 16 9 11 13 13
52 47 100 100 93 55 63 51 66 40 57
16 17 22 25 25 22 26 21 22 18 21
11 13 6 8 8 3 14 8 10 3 8
20 13 14 34 15 25 41 17 25 15 19
50 49 59 55 65 64 71 69 60 60 63
98 96 100 80 100 85 100 100 92 97 97
PPSV-23, 23-valent pneumococcal polysaccharide vaccine. Adult PPSV-23 program initiated in May 2010. Seasonal influenza vaccine provided in 2008 and 2009. Combined seasonal and H1N1 influenza vaccine provided in 2010 through 2012. PCV-13, 13-valent pneumococcal conjugate vaccine. Pediatric PCV-13 program initiated in December 2010.
doses of PCV-13, with coverage ranging between 80 and 100% by municipality (Table 1). Nicaragua performed routine influenza immunization throughout all of the years studied (2008–2012), with seasonal influenza vaccines offered in 2008 and 2009, and combined seasonal and H1N1 influenza vaccines offered in 2010–2012. 2.6. Statistical analyses The outcomes examined were the incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, and all reported deaths due to pneumonia (including those occurring both within the hospital and reported in the community) among adults ages 50–64 years and 65 years and older before and after implementation of the combined pneumococcal immunization program in Nicaragua (2008–2009 vs. 2011–2012). Numbers of ambulatory visits for pneumonia, pneumonia hospitalizations, and reports of death due to pneumonia per week were extracted from the hospital epidemiology and SILAIS databases between January 2008 and December 2012. Counts of hospitalizations for pneumonia were separated from ambulatory visits for pneumonia. Emergency department visits that did not result in hospital admission were categorized as ambulatory visits, along with visits to primary care centers or health posts. Crude incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, deaths due to pneumonia, and corresponding 95% confidence intervals (CI) were estimated using log-linear Poisson regression. Exposure time was estimated by official population estimates by municipality for each year. To estimate incidence rate ratios (IRRs) and corresponding 95% CI for the vaccine period (2011–2012) versus the pre-vaccine period (2008–2009), log-linear Poisson regression with generalized estimating equations (GEE) was used to allow for possible correlation between individuals within municipality. In this analysis, data were excluded from 2010, a transitional year during which both the PCV-13 and PPSV-23 vaccine programs were being introduced. In addition, we controlled for: (1) age group, (2) municipality as one of three categories, (a) urban, (b) peri-urban, or (c) rural, to account for potential differences in health-seeking behavior by municipality and distance from the patient’s home municipality to the hospital, and (3) the proportion of adults who were immunized against influenza by year and municipality. To assess potential changes in health-care utilization over the years studied, GEE Poisson regression was also used to examine the IRR of health facility visits for an unrelated diagnosis, diarrhea, in the pre-vaccine and vaccine periods.
3. Results 3.1. Numbers of health facility visits for pneumonia and pneumonia-related deaths Total numbers of ambulatory visits for pneumonia, pneumonia hospitalizations, and pneumonia-related deaths in the pre-vaccine (2008–2009) and vaccine (2011–2012) periods are shown for the two age groups in Table 2. 3.2. Incidence rates of health facility visits for pneumonia and pneumonia-related mortality Crude incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, and pneumonia-related deaths by year are shown in Fig. 1. For each of these outcomes, the incidence rates are lower during the second year after the implementation of the combined immunization program (2012) as compared to the first year (2011). 3.3. Incidence rate ratios (IRRs) of health facility visits for pneumonia and pneumonia-related mortality The crude and adjusted IRR (IRRa) for the period after (2011–2012) versus before (2008–2009) introduction of the vaccines are shown in Table 3. The incidence rates of ambulatory visits showed no change between the pre-vaccine and vaccine periods [50–64-year olds: IRRa = 0.84 (95% CI: 0.60, 1.17); ≥65-year olds: IRRa = 0.81 (95% CI: 0.61, 1.06)]. In contrast, an increase in the incidence rate of pneumonia hospitalizations was observed in the vaccine period as compared to the prevaccine period [50–64-year olds: IRRa = 1.82 (95% CI: 1.36, 2.42); ≥65-year olds: IRRa = 2.07 (95% CI: 1.84, 2.33)]. The incidence rates of pneumonia-related mortality were significantly lower in the Table 2 Numbers of health facility visits for pneumonia and pneumonia-related deaths in the pre-vaccine and vaccine periodsa in León, Nicaragua. ≥65 years old
50–64 years old
Ambulatory visits Hospitalizations Deaths
Pre-vaccine
Vaccine
Pre-vaccine
Vaccine
637 32 14
666 58 8
589 90 63
548 183 29
a Pre-vaccine, January 2008–December 2009; Vaccine, January 2011–December 2012.
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vaccine period as compared to the pre-vaccine period for both age groups [50–64-year olds: IRRa = 0.73 (95% CI: 0.56, 0.94); ≥65-year olds: IRRa = 0.55 (95% CI: 0.43, 0.70)]. 3.4. Incidence rate ratios (IRRs) of health facility visits for an unrelated diagnosis, diarrhea The incidence rates for all health facility visits for diarrhea were compared between the pre-vaccine period and vaccine period. Among adults aged 50–64 years old, there was an increase in the incidence rate of health facility visits for diarrhea in the vaccine period as compared to the pre-vaccine period [IRRa = 1.45 (95% CI: 1.06, 2.00)]. Among adults aged 65 years and older, there was no significant change in the incidence rate of health facility visits for diarrhea between the two time periods [IRRa = 1.11 (95% CI: 0.87, 1.43)]. 4. Discussion
Fig. 1. Crude incidence rates by age group for each year studied.
During the two years after introduction of a combined pediatric and adult pneumococcal immunization program in León, Nicaragua, we observed a lower incidence rate of pneumoniarelated mortality in older adults. Adults aged 50–64 years experienced a 27% (95% CI: 6%, 44%) lower incidence rate of pneumonia-related deaths, and adults 65 years and older experienced a 45% (95% CI: 30%, 57%) lower incidence rate of pneumonia-related deaths. While the incidence rate of ambulatory visits for pneumonia did not change in the vaccine years as compared to the pre-vaccine years, the incidence rate of hospitalizations for pneumonia actually increased during the vaccine years. Following PCV introduction in the US, the oldest adults (≥85 years old) experienced a 9% lower incidence of pneumonia hospitalizations during the first 5 years of the program, with more modest declines observed in adults aged 65–84, and a small increase observed in adults aged 40–64 [16]. In Nicaragua, the increase in hospitalizations for pneumonia may be a result of a gradual increase in health-care utilization among older adults following new federal legislation which removed costs associated with health facility visits in 2007. In comparison, total health facility visits for an unrelated diagnosis, diarrhea, also increased in the vaccine years among adults aged 50–64 years old. It is also possible that the combined immunization program may be effectively preventing the severest cases of pneumococcal pneumonia that may result in death, but may have less of an effect on mild-to-moderate pneumococcal disease that may result in a health facility visit. Incidence rates of pneumonia-related deaths, hospitalizations, and ambulatory visits were lower in the second year of the immunization program (2012) as compared to the first year (2011) (Fig. 1). This trend may be attributable to increasing coverage of PPSV-23 in adults, and possibly, herd protection from PCV-13. Rapid attainment of high coverage with PCV-13 may hasten the onset of herd protection of unimmunized age groups [26]. Coverage for 3 doses of PCV-13 in infants increased to 97% during the second year of the immunization program, as compared to 30% during the second year of the PCV-7 immunization program in the US [31]. In the
Table 3 Incidence rate ratios (IRRs) of ambulatory visits, hospitalizations, and pneumonia-related mortality in the pre-vaccine and vaccine periodsa by age group. ≥65 years old
50–64 years old
Ambulatory visits for pneumonia Hospitalizations for pneumonia Pneumonia-related mortalityb a b
Crude IRR
Adjusted IRR
Crude IRR
Adjusted IRR
0.97 (0.69, 1.35) 1.68 (1.27, 2.22) 0.52 (0.35, 0.78)
0.84 (0.60, 1.17) 1.82 (1.36, 2.42) 0.73 (0.56, 0.94)
0.93 (0.71, 1.23) 1.92 (1.65, 2.22) 0.42 (0.32, 0.58)
0.81 (0.61, 1.06) 2.07 (1.84, 2.33) 0.55 (0.43, 0.70)
Pre-vaccine, January 2008–December 2009; Vaccine, January 2011–December 2012. Interaction terms between age group and vaccine period were included in each model. For the adjusted mortality model only, this interaction was significant (p < 0.001).
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US, reductions in mortality from pneumococcal disease in older adults increased as pediatric PCV-7 coverage increased [32]. Due to the high pediatric coverage with PCV-13 in Nicaragua, herd protection may be contributing to reductions in pneumonia-related mortality in adults soon after introduction. If recommendations for the use of PCV-13 are broadened to include direct immunization of adults in coming years, there may be an additional tool available to protect older adults against pneumococcal pneumonia. As this was an observational study, we cannot prove that the changes observed were due to the immunization program. Continuing to follow trends in health facility visits and deaths due to pneumonia over the coming years will provide more convincing evidence for the impact of the immunization program in Nicaragua. Also, as an observational study, we cannot show the individual contributions of the PCV-13 versus the PPSV-23 immunization programs. Among our population, PCV-13 coverage was about double that of PPSV-23 coverage, due to the well-established pediatric immunization program. This higher coverage, in combination with prior evidence of a strong indirect effect of PCV-13, would support an important role of the PCV-13 immunization program in the observed changes in pneumonia-related mortality. However, the contribution of PPSV-23 in reducing bacteremic pneumonia in adults with low-risk factors [33] is likely contributing to the observed reduction in pneumonia-related mortality. A limitation of this study is that we cannot quantify the potential impact of annual variation in influenza transmission on our results. Nicaragua experienced the H1N1 pandemic in 2010, a year that was excluded from our analysis, as the transitional year in which the combined pneumococcal immunization program was implemented. Continued surveillance for pneumonia and pneumonia-related mortality in adults over additional years would be necessary to minimize the potential impact of annual variation of influenza transmission. While an influenza immunization program was in place during all of the years studied, the proportion of older adults who were immunized against influenza varied by year and municipality. To account for this, we controlled for the proportion of adults who received influenza immunization in the regression model. An additional limitation is that bacterial culturing is not routinely performed in the diagnosis of pneumonia in León, so we did not know the bacterial etiology of the pneumonia cases in the study. A prior study in León showed that S. pneumoniae was the most common cause of community-acquired pneumonia, detected in about 20% of cases [34], and therefore, a reduction in this most common pneumonia etiology should have an impact on overall incidence rates of pneumonia. 5. Conclusions These early results following introduction of a combined pediatric and adult pneumococcal immunization program in Nicaragua show a probable impact of the program on the reduction of pneumonia-related deaths in older adults, but a less clear impact on the reduction of health facility visits. Pneumococcal immunization should be considered by other Latin American countries to reduce the burden of pneumococcal disease among the growing population of older adults in the region. Funding This research was supported by an Investigator-Initiated Research (IIR) Award from Pfizer. The sponsors of the study had no role in the study design, data collection, statistical analysis, interpretation, or writing of the manuscript. The corresponding author was responsible for the content of the manuscript and the decision to submit for publication.
Conflicts of interest S.B.-D. has received investigator-initiated research grants from Pfizer and Merck. C.W. received a research grant from Novartis and has served as a consultant for Becton Dickinson and nanoMR. D.W. has served as a consultant for Pfizer, Merck, Clorox, Germitec, and Johnson & Johnson. Author contributions S.B.-D. designed the study, assisted with data analysis and interpretation of findings, and prepared the first draft of the paper. E.A., C.W., and D.W. assisted with study design, interpretation of findings, and manuscript preparation. L.L. performed the data analyses and reviewed the manuscript. J.R. and R.B. performed data collection, assisted with interpretation of findings, and reviewed the manuscript. G.M. and J.A. assisted with data collection, and reviewed the manuscript. M.H. supervised the data analysis and assisted with interpretation of findings and manuscript preparation. The final manuscript has been approved by all authors and there are no other persons who satisfy criteria for authorship but are not listed. Acknowledgements We would like to acknowledge the staff of the Sistemas Locales de Atención Integral a la Salud, León (SILAIS-León) and the Hospital Escuela Oscar Danilo Rosales Argüello (HEODRA). References [1] de Quadros CA. From global to regional: the importance of pneumococcal disease in Latin America. Vaccine 2009;27(Suppl 3):C29–32. [2] O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009;374(9693):893–902. [3] Weycker D, Strutton D, Edelsberg J, Sato R, Jackson LA. Clinical and economic burden of pneumococcal disease in older US adults. Vaccine 2010;28(31):4955–60. [4] Jackson ML, Neuzil KM, Thompson WW, Shay DK, Yu O, Hanson CA, et al. The burden of community-acquired pneumonia in seniors: results of a populationbased study. Clin Infect Dis 2004;39(11):1642–50. [5] Said MA, Johnson HL, Nonyane BA, Deloria-Knoll M, O’Brien KL, et al., AGEDD Adult Pneumococcal Burden Study Team. Estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques. PLoS One 2013;8(4):e60273. [6] Isturiz RE, Luna CM, Ramirez J. Clinical and economic burden of pneumonia among adults in Latin America. Int J Infect Dis 2010;14(10):e852–6. [7] Alanee SR, McGee L, Jackson D, Chiou CC, Feldman C, Morris AJ, et al. Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study. Clin Infect Dis 2007;45(1):46–51. [8] Burgos J, Luján M, Larrosa MN, Fontanals D, Bermudo GM, Planes A, et al. Risk factors for respiratory failure in pneumococcal pneumonia: the importance of pneumococcal serotypes. Eur Respir J 2014;43(2):545–53. [9] Buzzo AR, Roberts C, Mollinedo LG, Quevedo JM, Casas GL, Soldevilla JM. Morbidity and mortality of pneumonia in adults in six Latin American countries. Int J Infect Dis 2013;17(9):e673–7. [10] Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet 2007;369(9568):1179–86. [11] Jardine A, Menzies RI, McIntyre PB. Reduction in hospitalizations for pneumonia associated with the introduction of a pneumococcal conjugate vaccination schedule without a booster dose in Australia. Pediatr Infect Dis J 2010;29(7):607–12. [12] Koshy E, Murray J, Bottle A, Sharland M, Saxena S. Impact of the seven-valent pneumococcal conjugate vaccination (PCV7) programme on childhood hospital admissions for bacterial pneumonia and empyema in England: national timetrends study, 1997–2008. Thorax 2010;65(9):770–4. [13] Pírez MC, Algorta G, Cedrés A, Sobrero H, Varela A, Giachetto G, et al. Impact of universal pneumococcal vaccination on hospitalizations for pneumonia and meningitis in children in Montevideo, Uruguay. Pediatr Infect Dis J 2011;30(8):669–74. [14] Ho PL, Chiu SS, Chow FK, Mak GC, Lau YL. Pediatric hospitalization for pneumococcal diseases preventable by 7-valent pneumococcal conjugate vaccine in Hong Kong. Vaccine 2007 Sep 28;25(39-40):6837–41.
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Impact of a combined pediatric and adult pneumococcal immunization program on adult pneumonia incidence and mortality in Nicaragua ˜ e, Sylvia Becker-Dreps a,∗ , Erick Amaya b , Lan Liu c , Julio Rocha d , Rafaela Briceno e d c ´ , Michael G. Hudgens , Christopher W. Woods f , Gilberto Moreno , Jorge Aleman David J. Weber a a
University of North Carolina School of Medicine, Chapel Hill, NC, USA National Autonomous University of Nicaragua, León, Nicaragua c UNC Gillings School of Global Public Health, Chapel Hill, NC, USA d Hospital Escuela Oscar Danilo Rosales Argüello (HEODRA), León, Nicaragua e Sistemas Locales de Atención Integral a la Salud, León (SILAIS-León), León, Nicaragua f Duke University School of Medicine, Durham, NC, USA b
a r t i c l e
i n f o
Article history: Received 1 April 2014 Received in revised form 20 September 2014 Accepted 6 October 2014 Available online 4 November 2014 Keywords: Adults Nicaragua Pneumonia Pneumococcal vaccine Streptococcus pneumoniae.
a b s t r a c t Background: In 2010, Nicaragua implemented an adult immunization program with the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and a pediatric immunization program with the 13-valent pneumococcal conjugate vaccine (PCV-13). We assessed incidence rates of ambulatory visits and hospitalizations for pneumonia and pneumonia-related mortality in adults over the age of 50 years before and after the program’s implementation in the Department of León, Nicaragua. Methods: We collected visit diagnoses from all 107 public health facilities between 2008 and 2012 in León. We compared incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, and pneumonia-related mortality in the pre-vaccine (2008–2009) and vaccine (2011–2012) periods among older adults using Poisson regression with generalized estimating equations (GEE), controlling for age group, municipality, and proportions of adults who were immunized against influenza. Exposure time was estimated by official municipality population estimates. Results: We did not observe lower incidence rates of ambulatory visits or hospitalizations for pneumonia among adults during the vaccine period versus the pre-vaccine period. However, pneumonia-related mortality was lower in the vaccine period versus the pre-vaccine period, with an adjusted incidence rate ratio (IRRa) of 0.73 (0.56, 0.94) among adults aged 50–64 years, and 0.55 (0.43, 0.70) among adults aged ≥65 years. Conclusions: These early results following introduction of a combined pediatric and adult pneumococcal immunization program in Nicaragua show a probable impact of the program on the reduction of pneumonia-related deaths in older adults, but a less clear impact on the reduction of health facility visits for pneumonia. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Streptococcus pneumoniae remains a major cause of morbidity and mortality at both young and old extremes of life [1–4]. Among
∗ Corresponding author at: Department of Family Medicine, UNC School of Medicine, 590 Manning Drive, Chapel Hill, NC 27599-7595, USA. Tel.: +1 919 966 3711; fax: +1 919 966 6125. E-mail address: [email protected] (S. Becker-Dreps). http://dx.doi.org/10.1016/j.vaccine.2014.10.073 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
older adults in Latin America, community-acquired pneumonia is the third most common cause of mortality, and S. pneumoniae is the most frequently identified cause of pneumonia [5]. Without intervention, the burden of pneumococcal disease will increase as the Latin American population ages over coming decades, due to increased susceptibility to infection and higher risk of severe disease and complications from infection in this age group [6–9]. To reduce the burden of pneumococcal disease in children, many high-income countries (HICs) have implemented routine pediatric immunization with pneumococcal conjugate vaccines (PCVs).
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These pediatric PCV immunization programs have reduced the burden of pneumococcal disease among children [10–15], but have also lowered the incidence of pneumonia and pneumococcal colonization by vaccine serotypes in adults [16–18]. In light of this evidence of herd protection of adults, and also due to the incomplete protective effect of the pneumococcal polysaccharide vaccine (PPSV-23) in target groups [19,20], the WHO currently recommends the prioritization of pediatric PCV immunization programs in resource-limited settings [21,22]. The Nicaraguan Ministry of Health began a pediatric pneumococcal immunization program with the 13-valent pneumococcal conjugate vaccine (PCV-13, intramuscular, Pfizer) in December 2010 with a “3 + 0” dosing schedule, adding to the existing National Immunization Schedule [23]. Earlier the same year, due to a vaccine donation, the Ministry of Health also began offering a single dose of PPSV-23 (Merck, intramuscular) to adults aged 50 years and older. For both of these age groups, the pre-vaccine burden of pneumococcal disease and distribution of circulating pneumococcal serotypes is largely unknown in Nicaragua, as in many other low-middle income countries (LMICs). Also, individuals in LMICs may have differences in the immune response to vaccines as compared to HIC individuals, as has been observed with certain oral vaccines [24,25]. A prior study examined the impact of Nicaragua’s pneumococcal immunization program on children and found an estimated 30% reduction in hospitalizations due to pneumonia among age groups eligible to receive PCV-13 [26]. The goal of this study was to examine the overall effect [27] of the combined child and adult pneumococcal immunization program: the change in the incidence rate of health facility visits and deaths due to pneumonia in older adults before and after the program’s implementation.
2. Methods 2.1. Setting This ecological study was conducted in the Department of León in western Nicaragua. Nicaragua is an LMIC in Central America with a per capita GNI of $1650 [28]. Despite its low per capita GNI, Nicaragua has a well-functioning National Immunization Program, with adequate cold storage capacity [29]. Beginning in 2007, new federal legislation increased the population’s accessibility to public facilities by removing costs associated with clinic visits and hospitalizations. The Department of León, where the study was conducted, includes the country’s second largest city, León (2012 estimated city population: 193,598), five peri-urban municipalities, and four rural municipalities (2012 estimated department population: 396,969).
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facilities was de-identified, analysis of this data was determined to be exempt from full IRB review. 2.3. Assignment of diagnosis codes and information management The diagnoses of interest to this study include pneumonia and death due to pneumonia. Hospital diagnosis codes are assigned at the time of admission by the medical team admitting the patient and are maintained by the hospital epidemiology office in an electronic database. Similarly, emergency department visit codes are assigned by the medical team treating the patient in the emergency department. The definition of pneumonia used by hospital physicians is defined on page 72 of the Ministry of Health’s Management Protocol of Common Medical Problems in Adults [30], as an infectious syndrome including respiratory and constitutional symptoms, present with physical exam findings of consolidation, with confirmation of infiltrates on a chest radiograph. According to the Management Protocol and HEODRA protocols, all patients admitted for pneumonia are required to receive a chest radiograph. If a patient admitted with the diagnosis of pneumonia dies from pneumonia during the hospitalization or if a patient arrives to the HEODRA emergency department and dies prior to admission, a report of hospital death due to pneumonia is recorded. The database includes the date of admission, gender, age group, and municipality of origin. Data are entered into the electronic database within 1 week of presenting to the hospital. Ambulatory visit diagnosis codes are assigned by the health care provider caring for the patient and are maintained in an electronic database at the epidemiology office of the local health ministry, or, Sistemas Locales de Atención Integral a la Salud-León (SILAISLeón). The definition of pneumonia used by the ambulatory primary care providers includes the same clinical signs and symptoms as described above, but typically does not include chest radiography, as this is not available in the majority of settings. Deaths occurring outside the hospital are investigated by a team including a physician from SILAIS-León, the local physician, and an epidemiologist. If the team determines that the cause of death is pneumonia, a report of death due to pneumonia is entered into the electronic database. The database includes information on the date of the visit or report, gender, age group, and municipality of origin. 2.4. Population estimates The national census is performed every 10 years by the Nicaraguan Institute of Development Information (INIDE), with the last census occurring in 2005. Official population estimates by age group for each municipality are provided for intervening years by SILAIS-León. 2.5. Vaccine coverage by municipality
2.2. Health facilities Hospital data were collected at the single public referral hospital in the department of León, Hospital Escuela Oscar Danilo Rosales ¨ Arguello (HEODRA). During the years studied (2008–2012), the numbers of all-cause hospitalizations at HEODRA remained relatively stable with a low of 21,627 in 2008 and a high of 23,155 in 2010. Ambulatory visit data were collected from the 106 public primary care facilities (primary care centers and health posts) in the department in addition to the emergency department of HEODRA. Both public primary care facilities and public hospitals are under a government mandate to report visits for pneumonia to their departmental epidemiology office. The local health ministry estimates that 10% of the population access private health facilities instead of public health facilities. As data obtained from health
The National Immunization Program maintains data on immunization coverage by year and age group for each routinely administered vaccine. The PPSV-23 adult immunization program began in May 2010. The proportion of the adult population who were immunized with PPSV-23 by municipality and year are shown in Table 1. At the end of the first year of the PPSV-23 immunization program (2010), coverage with PPSV-23 among adults over age 50 varied between 25 and 29% by municipality. If we assume that the population was stable, coverage with PPSV-23 by the end of 2012 would be approximately 50%. The PCV-13 pediatric immunization program began in December 2010. By the end of 2011, 63% of infants in the department of León had received three doses of PCV-13, with coverage ranging between 49 and 71% by municipality. By the end of 2012, 97% of infants in the department had received three
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Table 1 Proportion of population (%) immunized each year by municipality. Municipality
Adults over age 50 years
Infants
PPSV-23a
Achuapa El Sauce Santa Rosa Jicaral Larreynega Telica Quezalguaque León La Paz Centro Nagarote All Municipalities a b c d
PCV-13d
Influenza
2010
2011
2012
2008b
2009
2010c
2011
2012
2011
2012
27 27 27 28 29 27 27 26 27 25 27
18 13 18 18 13 22 13 12 21 17 15
12 14 15 12 15 12 13 9 12 10 11
9 8 14 13 25 3 16 9 11 13 13
52 47 100 100 93 55 63 51 66 40 57
16 17 22 25 25 22 26 21 22 18 21
11 13 6 8 8 3 14 8 10 3 8
20 13 14 34 15 25 41 17 25 15 19
50 49 59 55 65 64 71 69 60 60 63
98 96 100 80 100 85 100 100 92 97 97
PPSV-23, 23-valent pneumococcal polysaccharide vaccine. Adult PPSV-23 program initiated in May 2010. Seasonal influenza vaccine provided in 2008 and 2009. Combined seasonal and H1N1 influenza vaccine provided in 2010 through 2012. PCV-13, 13-valent pneumococcal conjugate vaccine. Pediatric PCV-13 program initiated in December 2010.
doses of PCV-13, with coverage ranging between 80 and 100% by municipality (Table 1). Nicaragua performed routine influenza immunization throughout all of the years studied (2008–2012), with seasonal influenza vaccines offered in 2008 and 2009, and combined seasonal and H1N1 influenza vaccines offered in 2010–2012. 2.6. Statistical analyses The outcomes examined were the incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, and all reported deaths due to pneumonia (including those occurring both within the hospital and reported in the community) among adults ages 50–64 years and 65 years and older before and after implementation of the combined pneumococcal immunization program in Nicaragua (2008–2009 vs. 2011–2012). Numbers of ambulatory visits for pneumonia, pneumonia hospitalizations, and reports of death due to pneumonia per week were extracted from the hospital epidemiology and SILAIS databases between January 2008 and December 2012. Counts of hospitalizations for pneumonia were separated from ambulatory visits for pneumonia. Emergency department visits that did not result in hospital admission were categorized as ambulatory visits, along with visits to primary care centers or health posts. Crude incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, deaths due to pneumonia, and corresponding 95% confidence intervals (CI) were estimated using log-linear Poisson regression. Exposure time was estimated by official population estimates by municipality for each year. To estimate incidence rate ratios (IRRs) and corresponding 95% CI for the vaccine period (2011–2012) versus the pre-vaccine period (2008–2009), log-linear Poisson regression with generalized estimating equations (GEE) was used to allow for possible correlation between individuals within municipality. In this analysis, data were excluded from 2010, a transitional year during which both the PCV-13 and PPSV-23 vaccine programs were being introduced. In addition, we controlled for: (1) age group, (2) municipality as one of three categories, (a) urban, (b) peri-urban, or (c) rural, to account for potential differences in health-seeking behavior by municipality and distance from the patient’s home municipality to the hospital, and (3) the proportion of adults who were immunized against influenza by year and municipality. To assess potential changes in health-care utilization over the years studied, GEE Poisson regression was also used to examine the IRR of health facility visits for an unrelated diagnosis, diarrhea, in the pre-vaccine and vaccine periods.
3. Results 3.1. Numbers of health facility visits for pneumonia and pneumonia-related deaths Total numbers of ambulatory visits for pneumonia, pneumonia hospitalizations, and pneumonia-related deaths in the pre-vaccine (2008–2009) and vaccine (2011–2012) periods are shown for the two age groups in Table 2. 3.2. Incidence rates of health facility visits for pneumonia and pneumonia-related mortality Crude incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, and pneumonia-related deaths by year are shown in Fig. 1. For each of these outcomes, the incidence rates are lower during the second year after the implementation of the combined immunization program (2012) as compared to the first year (2011). 3.3. Incidence rate ratios (IRRs) of health facility visits for pneumonia and pneumonia-related mortality The crude and adjusted IRR (IRRa) for the period after (2011–2012) versus before (2008–2009) introduction of the vaccines are shown in Table 3. The incidence rates of ambulatory visits showed no change between the pre-vaccine and vaccine periods [50–64-year olds: IRRa = 0.84 (95% CI: 0.60, 1.17); ≥65-year olds: IRRa = 0.81 (95% CI: 0.61, 1.06)]. In contrast, an increase in the incidence rate of pneumonia hospitalizations was observed in the vaccine period as compared to the prevaccine period [50–64-year olds: IRRa = 1.82 (95% CI: 1.36, 2.42); ≥65-year olds: IRRa = 2.07 (95% CI: 1.84, 2.33)]. The incidence rates of pneumonia-related mortality were significantly lower in the Table 2 Numbers of health facility visits for pneumonia and pneumonia-related deaths in the pre-vaccine and vaccine periodsa in León, Nicaragua. ≥65 years old
50–64 years old
Ambulatory visits Hospitalizations Deaths
Pre-vaccine
Vaccine
Pre-vaccine
Vaccine
637 32 14
666 58 8
589 90 63
548 183 29
a Pre-vaccine, January 2008–December 2009; Vaccine, January 2011–December 2012.
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vaccine period as compared to the pre-vaccine period for both age groups [50–64-year olds: IRRa = 0.73 (95% CI: 0.56, 0.94); ≥65-year olds: IRRa = 0.55 (95% CI: 0.43, 0.70)]. 3.4. Incidence rate ratios (IRRs) of health facility visits for an unrelated diagnosis, diarrhea The incidence rates for all health facility visits for diarrhea were compared between the pre-vaccine period and vaccine period. Among adults aged 50–64 years old, there was an increase in the incidence rate of health facility visits for diarrhea in the vaccine period as compared to the pre-vaccine period [IRRa = 1.45 (95% CI: 1.06, 2.00)]. Among adults aged 65 years and older, there was no significant change in the incidence rate of health facility visits for diarrhea between the two time periods [IRRa = 1.11 (95% CI: 0.87, 1.43)]. 4. Discussion
Fig. 1. Crude incidence rates by age group for each year studied.
During the two years after introduction of a combined pediatric and adult pneumococcal immunization program in León, Nicaragua, we observed a lower incidence rate of pneumoniarelated mortality in older adults. Adults aged 50–64 years experienced a 27% (95% CI: 6%, 44%) lower incidence rate of pneumonia-related deaths, and adults 65 years and older experienced a 45% (95% CI: 30%, 57%) lower incidence rate of pneumonia-related deaths. While the incidence rate of ambulatory visits for pneumonia did not change in the vaccine years as compared to the pre-vaccine years, the incidence rate of hospitalizations for pneumonia actually increased during the vaccine years. Following PCV introduction in the US, the oldest adults (≥85 years old) experienced a 9% lower incidence of pneumonia hospitalizations during the first 5 years of the program, with more modest declines observed in adults aged 65–84, and a small increase observed in adults aged 40–64 [16]. In Nicaragua, the increase in hospitalizations for pneumonia may be a result of a gradual increase in health-care utilization among older adults following new federal legislation which removed costs associated with health facility visits in 2007. In comparison, total health facility visits for an unrelated diagnosis, diarrhea, also increased in the vaccine years among adults aged 50–64 years old. It is also possible that the combined immunization program may be effectively preventing the severest cases of pneumococcal pneumonia that may result in death, but may have less of an effect on mild-to-moderate pneumococcal disease that may result in a health facility visit. Incidence rates of pneumonia-related deaths, hospitalizations, and ambulatory visits were lower in the second year of the immunization program (2012) as compared to the first year (2011) (Fig. 1). This trend may be attributable to increasing coverage of PPSV-23 in adults, and possibly, herd protection from PCV-13. Rapid attainment of high coverage with PCV-13 may hasten the onset of herd protection of unimmunized age groups [26]. Coverage for 3 doses of PCV-13 in infants increased to 97% during the second year of the immunization program, as compared to 30% during the second year of the PCV-7 immunization program in the US [31]. In the
Table 3 Incidence rate ratios (IRRs) of ambulatory visits, hospitalizations, and pneumonia-related mortality in the pre-vaccine and vaccine periodsa by age group. ≥65 years old
50–64 years old
Ambulatory visits for pneumonia Hospitalizations for pneumonia Pneumonia-related mortalityb a b
Crude IRR
Adjusted IRR
Crude IRR
Adjusted IRR
0.97 (0.69, 1.35) 1.68 (1.27, 2.22) 0.52 (0.35, 0.78)
0.84 (0.60, 1.17) 1.82 (1.36, 2.42) 0.73 (0.56, 0.94)
0.93 (0.71, 1.23) 1.92 (1.65, 2.22) 0.42 (0.32, 0.58)
0.81 (0.61, 1.06) 2.07 (1.84, 2.33) 0.55 (0.43, 0.70)
Pre-vaccine, January 2008–December 2009; Vaccine, January 2011–December 2012. Interaction terms between age group and vaccine period were included in each model. For the adjusted mortality model only, this interaction was significant (p < 0.001).
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US, reductions in mortality from pneumococcal disease in older adults increased as pediatric PCV-7 coverage increased [32]. Due to the high pediatric coverage with PCV-13 in Nicaragua, herd protection may be contributing to reductions in pneumonia-related mortality in adults soon after introduction. If recommendations for the use of PCV-13 are broadened to include direct immunization of adults in coming years, there may be an additional tool available to protect older adults against pneumococcal pneumonia. As this was an observational study, we cannot prove that the changes observed were due to the immunization program. Continuing to follow trends in health facility visits and deaths due to pneumonia over the coming years will provide more convincing evidence for the impact of the immunization program in Nicaragua. Also, as an observational study, we cannot show the individual contributions of the PCV-13 versus the PPSV-23 immunization programs. Among our population, PCV-13 coverage was about double that of PPSV-23 coverage, due to the well-established pediatric immunization program. This higher coverage, in combination with prior evidence of a strong indirect effect of PCV-13, would support an important role of the PCV-13 immunization program in the observed changes in pneumonia-related mortality. However, the contribution of PPSV-23 in reducing bacteremic pneumonia in adults with low-risk factors [33] is likely contributing to the observed reduction in pneumonia-related mortality. A limitation of this study is that we cannot quantify the potential impact of annual variation in influenza transmission on our results. Nicaragua experienced the H1N1 pandemic in 2010, a year that was excluded from our analysis, as the transitional year in which the combined pneumococcal immunization program was implemented. Continued surveillance for pneumonia and pneumonia-related mortality in adults over additional years would be necessary to minimize the potential impact of annual variation of influenza transmission. While an influenza immunization program was in place during all of the years studied, the proportion of older adults who were immunized against influenza varied by year and municipality. To account for this, we controlled for the proportion of adults who received influenza immunization in the regression model. An additional limitation is that bacterial culturing is not routinely performed in the diagnosis of pneumonia in León, so we did not know the bacterial etiology of the pneumonia cases in the study. A prior study in León showed that S. pneumoniae was the most common cause of community-acquired pneumonia, detected in about 20% of cases [34], and therefore, a reduction in this most common pneumonia etiology should have an impact on overall incidence rates of pneumonia. 5. Conclusions These early results following introduction of a combined pediatric and adult pneumococcal immunization program in Nicaragua show a probable impact of the program on the reduction of pneumonia-related deaths in older adults, but a less clear impact on the reduction of health facility visits. Pneumococcal immunization should be considered by other Latin American countries to reduce the burden of pneumococcal disease among the growing population of older adults in the region. Funding This research was supported by an Investigator-Initiated Research (IIR) Award from Pfizer. The sponsors of the study had no role in the study design, data collection, statistical analysis, interpretation, or writing of the manuscript. The corresponding author was responsible for the content of the manuscript and the decision to submit for publication.
Conflicts of interest S.B.-D. has received investigator-initiated research grants from Pfizer and Merck. C.W. received a research grant from Novartis and has served as a consultant for Becton Dickinson and nanoMR. D.W. has served as a consultant for Pfizer, Merck, Clorox, Germitec, and Johnson & Johnson. Author contributions S.B.-D. designed the study, assisted with data analysis and interpretation of findings, and prepared the first draft of the paper. E.A., C.W., and D.W. assisted with study design, interpretation of findings, and manuscript preparation. L.L. performed the data analyses and reviewed the manuscript. J.R. and R.B. performed data collection, assisted with interpretation of findings, and reviewed the manuscript. G.M. and J.A. assisted with data collection, and reviewed the manuscript. M.H. supervised the data analysis and assisted with interpretation of findings and manuscript preparation. The final manuscript has been approved by all authors and there are no other persons who satisfy criteria for authorship but are not listed. Acknowledgements We would like to acknowledge the staff of the Sistemas Locales de Atención Integral a la Salud, León (SILAIS-León) and the Hospital Escuela Oscar Danilo Rosales Argüello (HEODRA). References [1] de Quadros CA. From global to regional: the importance of pneumococcal disease in Latin America. Vaccine 2009;27(Suppl 3):C29–32. [2] O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009;374(9693):893–902. [3] Weycker D, Strutton D, Edelsberg J, Sato R, Jackson LA. Clinical and economic burden of pneumococcal disease in older US adults. Vaccine 2010;28(31):4955–60. [4] Jackson ML, Neuzil KM, Thompson WW, Shay DK, Yu O, Hanson CA, et al. The burden of community-acquired pneumonia in seniors: results of a populationbased study. Clin Infect Dis 2004;39(11):1642–50. [5] Said MA, Johnson HL, Nonyane BA, Deloria-Knoll M, O’Brien KL, et al., AGEDD Adult Pneumococcal Burden Study Team. Estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques. PLoS One 2013;8(4):e60273. [6] Isturiz RE, Luna CM, Ramirez J. Clinical and economic burden of pneumonia among adults in Latin America. Int J Infect Dis 2010;14(10):e852–6. [7] Alanee SR, McGee L, Jackson D, Chiou CC, Feldman C, Morris AJ, et al. Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study. Clin Infect Dis 2007;45(1):46–51. [8] Burgos J, Luján M, Larrosa MN, Fontanals D, Bermudo GM, Planes A, et al. Risk factors for respiratory failure in pneumococcal pneumonia: the importance of pneumococcal serotypes. Eur Respir J 2014;43(2):545–53. [9] Buzzo AR, Roberts C, Mollinedo LG, Quevedo JM, Casas GL, Soldevilla JM. Morbidity and mortality of pneumonia in adults in six Latin American countries. Int J Infect Dis 2013;17(9):e673–7. [10] Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet 2007;369(9568):1179–86. [11] Jardine A, Menzies RI, McIntyre PB. Reduction in hospitalizations for pneumonia associated with the introduction of a pneumococcal conjugate vaccination schedule without a booster dose in Australia. Pediatr Infect Dis J 2010;29(7):607–12. [12] Koshy E, Murray J, Bottle A, Sharland M, Saxena S. Impact of the seven-valent pneumococcal conjugate vaccination (PCV7) programme on childhood hospital admissions for bacterial pneumonia and empyema in England: national timetrends study, 1997–2008. Thorax 2010;65(9):770–4. [13] Pírez MC, Algorta G, Cedrés A, Sobrero H, Varela A, Giachetto G, et al. Impact of universal pneumococcal vaccination on hospitalizations for pneumonia and meningitis in children in Montevideo, Uruguay. Pediatr Infect Dis J 2011;30(8):669–74. [14] Ho PL, Chiu SS, Chow FK, Mak GC, Lau YL. Pediatric hospitalization for pneumococcal diseases preventable by 7-valent pneumococcal conjugate vaccine in Hong Kong. Vaccine 2007 Sep 28;25(39-40):6837–41.
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