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Epidemiological burden of invasive pneumococcal disease in children and adolescents with predisposing risk factors

Open AccessPublished:June 29, 2015DOI:https://doi.org/10.1016/j.ijid.2015.06.016

      Highlights

      • Total population at risk ranged from 17.3 to 64.6 million.
      • According to SIREVA 2012, PCV13 offered a 62.9% coverage in Latin America.
      • Potentially covered population was 10,906,356-40,622,078 with PCV13.
      • Hypothetical immunized population ranged from 11.4 to 42.4 million, approximately.
      • Vaccinating against IPD in high-risk individuals is a major opportunity.

      Summary

      Objective

      Some medical conditions constitute important risk factors for the development of invasive pneumococcal diseases in children and adolescents aged from 5 to 19 years. Conjugate vaccines have potential efficacy in this scenario, but are not available in many Latin American public healthcare systems for this age group. This study aimed to estimate the preventable fraction of invasive pneumococcal diseases among individuals aged from 5 to 19 years with associated risk factors for its development.

      Methods

      Data regarding the Latin America population, risk factors prevalence and conjugate vaccines efficacy were obtained from the literature.

      Results

      Total population at risk ranged from 17.3 to 64.6 million of individuals and asthma was the most impacting risk factor. According to SIREVA, PCV13 provided a 62.9% serotypes coverage in individuals from 5 to 29 years in 2012, potentially increasing the covered population from [8,338,457-31,057,620] with PCV10 to [10,906,356-40,622,078] with PCV13. To date, according to available efficacy data, the hypothetically immunized population ranged from 11.4 to 42.4 million, representing 7.0% to 26.0% of the total population in this age group.

      Conclusions

      Vaccination in risk groups should be encouraged, as it potentially contributes to the reduction in the number of cases of invasive pneumococcal disease.

      Keywords

      1. Introduction

      Despite the current scenario of population aging and the predominance of chronic degenerative diseases as the main cause of death, invasive pneumococcal diseases (IPD) (meningitis, bacterial pneumonia and bacteremia/sepsis) still constitute a major cause of mortality in Latin America (LA), especially among children and elderly people.
      • Valenzuela M.T.
      • O’Loughlin R.
      • De La Hoz F.
      • Gomez E.
      • Constenla D.
      • Sinha A.
      • et al.
      The burden of pneumococcal disease among Latin American and Caribbean children: review of the evidence.
      Streptococcus pneumoniae is the most prevalent etiologic agent associated with pneumonia cases in LA, accounting for 11.08% of all disease causes.
      • Gentile A.
      • Bardach A.
      • Ciapponi A.
      • Garcia-Marti S.
      • Aruj P.
      • Glujovsky D.
      • et al.
      Epidemiology of community-acquired pneumonia in children of Latin America and the Caribbean: a systematic review and meta-analysis.
      The average incidence of pneumococcal pneumonia is estimated at 918 cases per 100,000 child-years in the age group of up to five years.
      • Gentile A.
      • Bardach A.
      • Ciapponi A.
      • Garcia-Marti S.
      • Aruj P.
      • Glujovsky D.
      • et al.
      Epidemiology of community-acquired pneumonia in children of Latin America and the Caribbean: a systematic review and meta-analysis.
      Pneumonia associated mortality for any etiologic agent in adults over 50 years is estimated at 17.7%, with 20-60% of cases related to S. pneumoniae.
      • Buzzo A.R.
      • Roberts C.
      • Mollinedo L.G.
      • Quevedo J.M.
      • Casas G.L.
      • Soldevilla J.M.
      Morbidity and mortality of pneumonia in adults in six Latin American countries.
      In addition, bacteremia may occur in up to 30% of patients with pneumococcal pneumonia, with 20% mortality in children, reaching up to 60% in the elderly.
      • Centers for Disease Control and Prevention (CDC)
      Pneumococcal disease.
      Pneumococcal meningitis is also a relevant issue in LA. It is estimated that 6.0% of all meningitis are due to pneumococcus. The incidence in this context is an average of 8.34/100,000 in children aged 0-23 months, and 4.62/100,000 in the age group of up to five years. The mortality rate is high among the elderly reaching 80% and ranges from 1.8% to 14.9% among children aged up to 59 months.
      • Centers for Disease Control and Prevention (CDC)
      Pneumococcal disease.
      • Ciapponi A.
      • Elorriaga N.
      • Rojas J.I.
      • Romano M.
      • Martí S.G.
      • Bardach A.
      • et al.
      Epidemiology of pediatric pneumococcal meningitis bacteremia in Latin America and the Caribbean: a systematic review meta-analysis.
      Serotypes 1, 3, 5, 6A/B, 7F, 9 V, 14, 18C, 19A/F, and 23F are the most frequently found in LA. These serotypes are covered by both conjugate vaccines (PCV7 contains 4, 6B, 9 V, 14, 18C, 19F and 23F serotypes; PCV10 also covers serotypes 1, 5 and 7F in addition to PCV7; and PCV13 contains serotypes 1, 3, 5, 6A, 7F and 19A in addition to PCV7) and the polysaccharide vaccine PPSV23 (serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9 V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F). Thus, despite the high incidence of IPD, available vaccines show potential efficacy in this scenario, setting up a preventable health problem in these countries.
      It is known that the incidence of IPD in children and adolescents aged 6 to 17 years is low.
      • Mitchell R.
      • Trück J.
      • Pollard A.J.
      Use of the 13-valent pneumococcal conjugate vaccine in children and adolescents aged 6-17 years.
      Nevertheless, the disease estimation in LA is incipient in this age range due the lack of active surveillance in that particular group. In addition, some medical conditions constitute important risk factors for this age group, such as renal failure, liver failure, chronic lung disease (including asthma), diabetes mellitus, asplenia, cancer, HIV and other diseases.

      Centers for Disease Control and Prevention, (CDC). Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children – Advisory Committee on Immunization Practices (ACIP) [Internet]. Morbidity and Mortality Weekly Report, 2010 [cited 2014 Sep 13]. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5909a2.htm.

      • Pelton S.
      • Weycker D.
      • Farkouh R.
      • Strutton D.
      • Shea K.
      • Edelsberg J.
      Risk of pneumococcal disease in children with chronic medical conditions in the era of pneumococcal conjugate vaccine.
      Despite this, little research has been carried out in LA and specifically in subjects aged up to 19 years in order to describe the incidence, prevalence, morbidity and additional risk factors for these subgroups. However, research performed in other fields has shown that PD incidence in these individuals is actually higher when compared to those without such conditions.
      • Muhammad R.D.
      • Oza-Frank R.
      • Zell E.
      • Link-Gelles R.
      • Narayan K.M.V.
      • Schaffner W.
      • et al.
      Epidemiology of invasive pneumococcal disease among high-risk adults since the introduction of pneumococcal conjugate vaccine for children.
      Examples include patients with diabetes, cancer, chronic pulmonary and cardiac diseases having IPD incidence estimated at 34.9 cases per 100,000 people. By comparison, IPD incidence for individuals with same age, but no risk factors was evaluated at 8.8/100,000.
      • Muhammad R.D.
      • Oza-Frank R.
      • Zell E.
      • Link-Gelles R.
      • Narayan K.M.V.
      • Schaffner W.
      • et al.
      Epidemiology of invasive pneumococcal disease among high-risk adults since the introduction of pneumococcal conjugate vaccine for children.
      In certain surveys conducted in the United States (US), IPD incidence ranged from 21.1 to 23.0/100,000 in adults with moderate to severe asthma.
      • Talbot T.R.
      • Hartert T.V.
      • Mitchel E.
      • Halasa N.B.
      • Arbogast P.G.
      • Poehling K.A.
      • et al.
      Asthma as a risk factor for invasive pneumococcal disease.
      • Flory J.H.
      • Joffe M.
      • Fishman N.O.
      • Edelstein P.H.
      • Metlay J.P.
      Socioeconomic risk factors for bacteraemic pneumococcal pneumonia in adults.
      However, in adults without asthma, incidence was estimated at 8.8/100,000.
      • Flory J.H.
      • Joffe M.
      • Fishman N.O.
      • Edelstein P.H.
      • Metlay J.P.
      Socioeconomic risk factors for bacteraemic pneumococcal pneumonia in adults.
      When asthmatic individuals aged 2-49 years were considered, IPD incidence was 42/100,000.
      • Flory J.H.
      • Joffe M.
      • Fishman N.O.
      • Edelstein P.H.
      • Metlay J.P.
      Socioeconomic risk factors for bacteraemic pneumococcal pneumonia in adults.
      This suggests that IPD incidence may be higher among asthmatic children and adolescents when compared to adults with the same condition. Regarding IPD prevalence, the magnitude varied from 17.1 to 17.7% in asthmatic children and adolescents aged 5-17 years vs. 5.5 to 8.1% among subjects with the same age, but without asthma.
      • Talbot T.R.
      • Hartert T.V.
      • Mitchel E.
      • Halasa N.B.
      • Arbogast P.G.
      • Poehling K.A.
      • et al.
      Asthma as a risk factor for invasive pneumococcal disease.
      Another commonly vulnerable subgroup to pneumococcal infections is end-stage renal disease. Among these patients, IPDs are the second cause of death and the leading cause of hospitalization. This situation takes place, in part, by uremia related to decrease of immune function, and also by exposure to infection through the dialysis catheter. The most common infections among them are urinary tract infections, sepsis and pneumonia.

      United States Renal Data System. U.S. Renal Data System 2009 Annual Data Report: Atlas of chronic kidney disease and end-stage renal disease in the United States. 2009.

      Subjects with any immunosuppressive condition are also particularly vulnerable to S. pneumoniae, including, therefore, positive HIV patients. IPD incidence in HIV positive individuals is estimated at 246/100,000 for those aged 15-44 years and is still higher among patients not using antiretroviral therapy (281/100,000) and those with severe immunosuppression (563/100,000).
      • Yin Z.
      • Rice B.D.
      • Waight P.
      • Miller E.
      • George R.
      • Brown A.E.
      • et al.
      Invasive pneumococcal disease among HIV-positive individuals 2000-2009.
      Sickle cell disease is also considered a risk factor for IPD development, besides presenting a worse prognosis when compared to individuals without the disease. In a US study with children and adolescents under 18 years old with sickle cell disease, they were more likely to be hospitalized (84%-92% vs. 31%-56%) and had higher risk to die (6%-17% vs. 1%-2%) when compared to children and adolescents with IPD, but without this additional risk factor.
      • Payne A.B.
      • Link-Gelles R.
      • Azonobi I.
      • Hooper W.C.
      • Beall B.W.
      • Jorgensen J.H.
      • et al.
      Invasive pneumococcal disease among children with and without sickle cell disease in the United States, 1998 to 2009.
      Van Hoek and colleagues reported that among children aged 2 to 15 years the presence of one or more risk factors is associated with a 11.7 times greater probability of developing IPD.
      • Van Hoek A.J.
      • Andrews N.
      • Waight P.
      • Stowe J.
      • Gates P.
      • George R.
      • et al.
      The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England.
      Among risk factors, diabetes mellitus incidence in adolescents is an important condition which implies a higher risk for developing bacteremia, invasive forms, and higher mortality. However, studies defining the risk magnitude only in individuals with diabetes are scarce.
      • Smith S.A.
      • Poland G.A.
      Use of influenza and pneumococcal vaccines in people with diabetes.
      Patients with risk factors mentioned above seem to benefit from vaccination against pneumococcus. Immunization of people highly vulnerable to IPD development is not performed in many LA countries. Such intervention represents an important strategy for reducing morbidity and mortality. Thus, this study aims to estimate the preventable fraction of IPD among children and adolescents from 5 to 19 years of age with a risk factor for their development.

      2. Material and methods

      The total population in LA was estimated from data provided by the Latin American and Caribbean Demographic Center (CELADE) for the year 2014.

      CELADE – División de Población de la CEPAL. Estimaciones y proyecciones de población a largo plazo. 1950-2100 – Revisión 2013. 2013.

      This included the following countries: Argentina, Plurinational State of Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Ecuador, El Salvador, Guatemala, Haiti, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Dominican Republic, Uruguay and Bolivarian Republic of Venezuela.
      Prevalence data (in percentage) for specific risk population was searched in the literature in order to calculate the preventable fraction of IPD in the Latin American population. We sought studies that evaluated the prevalence of pneumococcal disease in patients in high-risk groups. The electronic searches were conducted until July 2014 in the databases MEDLINE via PubMed and LILACS using the following terms combined in a variety of strategies: anatomic asplenia, functional asplenia, kidney diseases, HIV infection, asthma, diabetes mellitus, children and Latin America. Search engines additionally included Google®. Electronic searches were supplemented by manual searches of bibliographic references. Information extracted from abstracts was not considered.
      Thus, data on the prevalence of asthma, renal disease (dialysis patients), diabetes mellitus, sickle cell disease and HIV were applied to the total population in LA, and thus the risk population was obtained. When prevalence data were not available for the LA, information from other domains was used.
      The vaccine efficacy in specific risk population for each subgroup was used in order to calculate the preventable fraction. Calculations were performed by estimating the use of PCV13 conjugate vaccine, exclusively. Searches were conducted in the databases mentioned above, in the same period, using the following terms: pneumococcal vaccines, children and the diseases mentioned above. Currently, there is no data on PCV13 efficacy in pediatric patients at high-risk in published papers. Therefore, data regarding other conjugate vaccines was used. This scenario considered that all vulnerable population had access to immunization. The impact of herd immunity was not considered. Table S1 provides information of all articles used as a data source.

      3. Results

      CELADE stratifies individuals into five-year age groups, and therefore the analysis was performed considering the maximum age of 19 years. According to CELADE, 215,197,435 people are aged between 0 and 19 years in LA and 162,950,134 constitute the age group of 5-19 years.
      Table 1 shows the prevalence of asthma, renal disease, diabetes, sickle cell disease and HIV in four different age groups (0-4, 5-9, 10-14, and 15-19 years old).
      • Chong Neto H.J.
      • Rosário N.A.
      • Solé D.
      Asthma and rhinitis in South America: how different they are from other parts of the world.
      • Sesso R.C.
      • Lopes A.A.
      • Thomé F.S.
      • Lugon J.R.
      • Watanabe Y.
      • Santos D.R.
      Report of the Brazilian chronic dialysis census.
      • Aschner P.
      Diabetes trends in Latin America.
      • Lervolino L.G.
      • Baldin P.E.A.
      • Picado S.M.
      • Calil K.B.
      • Viel A.A.
      • Campos L.A.F.
      Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies.

      World Health Organization (WHO). Adult HIV prevalence (15–49 years), 2012 by WHO region [Internet]. 2012. Available from: http://www.who.int/gho/hiv/epidemic_status/prevalence/en/.

      In this analysis, subjects aged 5-19 years were considered. Risk populations according to prevalence rates are also available. Due the lack of prevalence information for certain age groups, the closer age available was used and generalized.
      Table 1Population at risk according to risk factors and age groups in Latin America
      Prevalence (%)Age group (years)Total population under risk

      (0-19)
      Total population under risk

      (5-19)
      Ref.
      0 – 45 – 910 – 1415 – 190 – 195-19
      Total population52,247,30253,313,66055,130,97754,505,497215,197,435162,950,13423,427,783 – 85,541,78017,340,529 – 64,586,955CELADE 2013

      CELADE – División de Población de la CEPAL. Estimaciones y proyecciones de población a largo plazo. 1950-2100 – Revisión 2013. 2013.

      Asthma
      Prevalence refers to 6-7 years and 13-14 years age groups in South America (lower limit, Bogota; upper limit, São Paulo West).
      10 – 31.210 – 31.28.5 – 30.58.5 – 30.510 – 31.2/8.5 – 30.510 – 31.2/8.5 – 30.519,875,196 – 66,374,14514,650,466 – 50,072,986Chong Neto 2012
      • Chong Neto H.J.
      • Rosário N.A.
      • Solé D.
      Asthma and rhinitis in South America: how different they are from other parts of the world.
      Renal diseases (dialysis)
      Prevalence calculated from the information provided by the Brazilian census of chronic dialysis.
      0.050.050.050.050.050.05107,59981,475Sesso 2012
      • Sesso R.C.
      • Lopes A.A.
      • Thomé F.S.
      • Lugon J.R.
      • Watanabe Y.
      • Santos D.R.
      Report of the Brazilian chronic dialysis census.
      Diabetes type 2
      The prevalence of type 2 diabetes in children and adolescents up to 15 years old in Latin America was considered. d The prevalence of sickle cell disease at birth in Brazil was considered.
      1.2 – 8.01.2 – 8.01.2 – 8.01.2 – 8.01.2 – 8.01.2 – 8.02,582,369 – 17,215,7951,955,402 – 13,036,011Aschner 2002
      • Aschner P.
      Diabetes trends in Latin America.
      Sickle cell disease0.00085 – 0.2570.00085 – 0.2570.00085 – 0.2570.00085 – 0.2570.00085 – 0.2570.00085 – 0.2571,829 – 553,0571,385 – 418,782Lervolino 2011
      • Lervolino L.G.
      • Baldin P.E.A.
      • Picado S.M.
      • Calil K.B.
      • Viel A.A.
      • Campos L.A.F.
      Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies.
      HIV
      Prevalence for the entire Latin America population, 15-49 years old.
      0.4 – 0.60.4 – 0.60.4 – 0.60.4 – 0.60.4 – 0.60.4 – 0.6860,790 – 1,291,185651,801 – 977,701WHO 2012

      World Health Organization (WHO). Adult HIV prevalence (15–49 years), 2012 by WHO region [Internet]. 2012. Available from: http://www.who.int/gho/hiv/epidemic_status/prevalence/en/.

      a Prevalence refers to 6-7 years and 13-14 years age groups in South America (lower limit, Bogota; upper limit, São Paulo West).
      b Prevalence calculated from the information provided by the Brazilian census of chronic dialysis.
      c The prevalence of type 2 diabetes in children and adolescents up to 15 years old in Latin America was considered.d The prevalence of sickle cell disease at birth in Brazil was considered.
      e Prevalence for the entire Latin America population, 15-49 years old.
      The total population at risk within the age group of interest ranged from 17.3 to 64.6 million, according to available data. Asthma was the risk factor with the greatest impact, with 14.6 million children and adolescents susceptible to IPD. Among the evaluated factors, sickle cell disease and renal disease presented the lowest impact on the total number of individuals at risk, with 1,385-418,782 (according to the prevalence data used), and 81,475 susceptible, respectively.
      Table 2 shows the number of subjects potentially covered by each conjugate vaccine. According to the Regional Vaccine System (SIREVA) 2012

      Organización Panamericana de la Salud. Informe Regional de SIREVA II, 2012: datos por país y por grupos de edad sobre las características de los aislamientos de Streptococcus pneumoniae, Haemophilus influenzae y Neisseria meningitidis, en procesos invasores. Washington, DC: OPAS; 2013.

      published in 2013, considering prevalent serotypes in LA and serotypes contained in conjugate vaccines, PCV10 offers a 48.1% coverage for individuals aged 5 to 29 years in LA and PCV13, a 62.9% coverage. Thus, potentially covered population increased from 8,338,457-31,057,620 patients with the use of PCV10 to 10,906,356-40,622,078 with PCV13.
      Table 2Population potentially covered by each conjugate vaccine available in Latin America
      Potentially covered population with the use of conjugate vaccines
      Coverage in the age group 5-29 years. PCV7=conjugate vaccine with 7 serotypes. PCV10=conjugate vaccine with 10 serotypes. PCV 13=conjugate vaccine with 13 serotypes.
      Population at risk (5 – 19 years)PCV10 (48.1% coverage)PCV13 (62.9% coverage)
      Total population17,340,529 – 64,586,9558,338,457 – 31,057,62010,906,356 – 40,622,078
      Asthma14,650,466 – 50,072,9867,044,900 – 24,078,3589,214,436 – 31,493,492
      Renal diseases (dialysis)81,47539,17851,244
      Diabetes type 21,955,402 – 13,036,011940,285 – 6,268,5641,229,854 – 8,199,022
      Sickle cell disease1,385 – 418,782666 – 201,378871 – 263,394
      HIV651,801 – 977,701313,428 – 470,142409,951 – 614,927
      Note: potential coverage data were obtained by serotypes prevalence in Latin America according to SIREVA 2012. PCV10 is not indicated for the age group analyzed, calculation made only for comparison.
      * Coverage in the age group 5-29 years. PCV7 = conjugate vaccine with 7 serotypes. PCV10 = conjugate vaccine with 10 serotypes. PCV 13 = conjugate vaccine with 13 serotypes.
      The number of subjects possibly immunized after PCV13 application using currently available efficacy data is presented in Table 3.
      • Klugman K.P.
      • Madhi S.A.
      • Huebner R.E.
      • Kohberger R.
      • Mbelle N.
      • Pierce N.
      A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.
      • Adamkiewicz T.V.
      • Silk B.J.
      • Howgate J.
      • Baughman W.
      • Strayhorn G.
      • Sullivan K.
      • et al.
      Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life.
      There is no data on PCV13 efficacy in children at high-risk in published papers, therefore, in children with sickle cell disease, efficacy of PCV7 was used. Moreover, the others groups were calculated by extrapolating data from the efficacy of PCV9 in HIV-infected children. In this scenario, the hypothetical immunized population ranged from 11.4 to 42.4 million, approximately. Individuals with asthma were the majority and accounted for 77.4% to 84.5% of individuals who would benefit from vaccination.
      Table 3Population at risk for pneumococcal diseases that would benefit from PCV13 application in Latin America
      Population at risk

      (5 – 19 years)
      Vaccine efficacy %

      (PCV)
      Potentially benefited individuals with lower risk of developing IPDReference
      Total population17,340,529 – 64,586,95511,358,266 – 42,371,042
      Asthma14,650,466 – 50,072,98665.0 l9,596,055 – 32,797,806Klugman 2003
      • Klugman K.P.
      • Madhi S.A.
      • Huebner R.E.
      • Kohberger R.
      • Mbelle N.
      • Pierce N.
      A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.
      Renal diseases (dialysis)81,47565.0 l53,366Klugman 2003
      • Klugman K.P.
      • Madhi S.A.
      • Huebner R.E.
      • Kohberger R.
      • Mbelle N.
      • Pierce N.
      A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.
      Diabetes type 21,955,402 – 13,036,01165.0 l1,280,788 – 8,538,587Klugman 2003
      • Klugman K.P.
      • Madhi S.A.
      • Huebner R.E.
      • Kohberger R.
      • Mbelle N.
      • Pierce N.
      A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.
      Sickle cell disease1,385 – 418,78281.4 m1,127 – 340,888Adamkiewicz 2008
      • Adamkiewicz T.V.
      • Silk B.J.
      • Howgate J.
      • Baughman W.
      • Strayhorn G.
      • Sullivan K.
      • et al.
      Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life.
      HIV651,801 – 977,70165.0 l426,929 – 640,394Klugman 2003
      • Klugman K.P.
      • Madhi S.A.
      • Huebner R.E.
      • Kohberger R.
      • Mbelle N.
      • Pierce N.
      A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.
      l Extrapolated data from the efficacy of PCV9 in HIV-infected children.
      m Efficacy of PCV7 evaluated in children with sickle cell disease.
      IPD = invasive pneumococcal diseases. PCV = pneumococcal conjugate vaccine.

      4. Discussion

      4.1 Generalization of the prevalence estimates

      To calculate the population who would be immunized for IPD, data on the prevalence of some risk factors, as well as conjugate vaccines efficacy, were generalized. These extrapolations were performed from a restricted to a wider domain, as well as between different age groups. The risk factors used in this study are just some of the factors associated with the development of pneumococcal disease. However, they were used because they were the available data at the time when the search was conducted in the literature.
      Regarding diabetes mellitus and HIV prevalence, data related to the population in LA were applied for all age groups, as the original information source did not provide it stratified by age. Also, type 2 diabetes mellitus data were used, specifically. Data found for type 1 diabetes mellitus was incidence, and was not considered. Regarding HIV, possibly the prevalence is higher among adolescents due to sexual transmission and drug use, compared to children, where transmission takes place vertically. Thus, the total population at risk due to HIV may have been overestimated among children 5-9 years. The same phenomenon may have occurred in type 2 diabetes mellitus, with the prevalence overestimated among children.
      Murray and colleagues estimated that people living with HIV in LA are 18.7% smaller than previously estimated.
      • Murray C.J.L.
      • Ortblad K.F.
      • Guinovart C.
      • Lim S.S.
      • Wolock T.M.
      • Roberts D.A.
      • et al.
      Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.
      In this scenario, the number of at-risk individuals could range from 529,914 to 794,871.
      In asthma, the data comes from the estimates obtained by the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three, an international multi-center cross-sectional study involving two age groups of school children, 13-14 year olds (adolescents) and 6-7 year olds (children).
      • Chong Neto H.J.
      • Rosário N.A.
      • Solé D.
      Asthma and rhinitis in South America: how different they are from other parts of the world.
      Being a population-based study, generalizability of these data to a wider field is plausible. In addition, some of the age groups were not covered. Thus, prevalence rates for these groups were repeated from available data. Due to these generalizations in prevalence data, the population at risk, as well as the immunized population, can be either underestimated or overestimated.
      Prevalence rates for chronic renal disease and sickle cell disease in LA were not found. Therefore, data were generalized from Brazilian studies, each one with its peculiarities.
      Data of children and adolescents on dialysis were obtained from the Brazilian census of chronic dialysis for children and adolescents up to 12 years.
      • Sesso R.C.
      • Lopes A.A.
      • Thomé F.S.
      • Lugon J.R.
      • Watanabe Y.
      • Santos D.R.
      Report of the Brazilian chronic dialysis census.
      This estimate was used in all age groups due to lack of stratification of age on the source of information. Even so, significant fluctuations of this prevalence by age group are not expected.
      Prevalence data for sickle cell disease was also originated from Brazilian population. Specific sickle cell disease information was used.
      • Lervolino L.G.
      • Baldin P.E.A.
      • Picado S.M.
      • Calil K.B.
      • Viel A.A.
      • Campos L.A.F.
      Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies.
      Since this is a genetic disease, variation among age groups is not floating. Nevertheless, the wide prevalence range is due to regional variation in Brazil.
      It should be considered that in healthy children the risk of IPD decreases with age, but in those at high-risk, it continues at the same pace.
      • Pelton S.
      • Weycker D.
      • Farkouh R.
      • Strutton D.
      • Shea K.
      • Edelsberg J.
      Risk of pneumococcal disease in children with chronic medical conditions in the era of pneumococcal conjugate vaccine.

      4.2 Generalization of conjugate vaccine efficacy

      Available literature data on PCV13 efficacy are restricted to children under five years and healthy adults over 50 years and with no immunosuppressive risk factors. Efficacy data with PCV10 and 13 are not available because they were not published. Previous works were made with PCV7. Thus, PCV7 data was used for patients with sickle cell disease and PCV9 for HIV-positive patients.
      • Klugman K.P.
      • Madhi S.A.
      • Huebner R.E.
      • Kohberger R.
      • Mbelle N.
      • Pierce N.
      A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.
      • Adamkiewicz T.V.
      • Silk B.J.
      • Howgate J.
      • Baughman W.
      • Strayhorn G.
      • Sullivan K.
      • et al.
      Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life.
      Due to lack of information on vaccine efficacy for other risk categories, these groups were determined using the vaccine efficacy in HIV patients. This strategy was used because HIV-patient data represents the lowest estimated vaccine efficacy available in the literature, in order to avoid an overestimated immunized population in these risk groups.

      4.3 Benefits for the population likely to be immunized and for general population

      Population that would benefit from conjugate vaccination considering PCV7/9 ranged from 11.4 to 42.4 million, accounting for 7.0-26.0% of the general population at this age group. This information is probably underestimated, as only some risk situations were evaluated among all the existing risk conditions for IPD. Nevertheless, immunization provides a large impact on that particular population. In addition to preventing IPD, immunization also prevents minor IPD as sinusitis and otitis, among others.
      • Eskola J.
      • Kilpi T.
      • Palmu A.
      • Jokinen J.
      • Haapakoski J.
      • Herva E.
      • et al.
      Efficacy of a pneumococcal conjugate vaccine against acute otitis media.

      4.4 Incorporation of vaccines for pneumococcal disease in different Latin American countries

      PCV7 was licensed in 2000 in order to provide protection against seven of the most common pneumococcal serotypes. In 2006, the World Health Organization (WHO) recommended the vaccine inclusion in all routine immunization programs, especially in countries with a high IPD burden, defined as >10% pneumonia attributed deaths in children aged <5 years or pneumonia mortality rate >50 deaths per 1,000 live births among children aged <5 years. In early 2010, new formulations with protection against 10 and 13 serotypes have become available for use.

      Centers for Disease Control and Prevention (CDC). Progress in introduction of pneumococcal conjugate vaccine – worldwide, 2000–2012 [Internet]. Morbidity and Mortality Weekly Report, 2013 [cited 2014 Sep 13]. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6216a4.htm?s_cid=mm6216a4_e.

      By 2014, the following countries in LA introduced the PCV in their national immunization programs: Costa Rica (2009); Mexico (2006), Uruguay (2007); Peru (2009); Brazil (2010), Ecuador (2010), El Salvador (2010), Panama (2010), Nicaragua (2011); Chile (2011), Colombia (2010), Honduras (2011), Argentina (2012), Guatemala (2012), Paraguay (2013), Dominican Republic (2013), Venezuela (2014) and Bolivia (2014).

      Pan American Health Organization (PAHO). Technical Advisory Group on vaccine - preventable diseases – final report. TAG Meeting. Buenos Aires; 2011. p. 49.

      República Dominicana. Incluyen vacuna contra neumococo al programa ampliado de inmunización [Internet]. Ministerio de Salud Publica. 2014 [cited 2014 Sep 13]. Available from: http://www.msp.gob.do/article/incluyen-vacuna-contra-neumococo-al-programa-ampliado-de-inmunizacion.

      República Bolivariana da Venezuela. Vacuna contra el neumococo reducirá la mortalidad infantil en Venezuela [Internet]. Ministerio del Poder Popular para la Comunicación y la Información. 2014 [cited 2014 Sep 13]. Available from: http://www.minci.gob.ve/2014/07/vacuna-contra-el-neumococo-reducira-la-mortalidad-infantil-en-venezuela/.

      Estado Plurinacional da Bolívia. Gobierno presenta vacuna “neumococos” [Internet]. 2014 [cited 2014 Sep 13]. Available from: http://www.bolivia.com/vida-sana/salud/sdi/80475/gobierno-presenta-vacuna-neumococos.

      • Ministério da Saúde (Brasil). Secretaria de Vigilância em Saúde
      Departamento de Vigilância Epidemiológica. Coordenação-Geral do Programa Nacional de Imunizações. Proposta para introdução da vacina pneumocócica 10-valente (conjugada) no calendário básico de vacinação da criança.

      4.5 Vaccines coverage for pneumococcal disease

      The immunization of high-risk population against IPD aged between 2 and 65 years has been conducted in several countries with the administration of PPSV23. However, immunocompromised patients do not present good response to polysaccharide vaccines, being conjugate vaccines the best option for this group.
      • World Health Organization (WHO)
      Pneumococcal conjugate vaccine for childhood immunization - WHO position paper.
      PCV10 contains the seven PCV7 serotypes plus three additional serotypes. However it is not indicated for subjects aged more than 5 years. PCV13 provides a wider coverage, since it includes six additional serotypes versus PCV7. According to SIREVA 2012, PCV10 presents 48.1% of coverage considering serotypes present in LA for individuals aged from 5 to 29 years. Therefore, considering the entire population at risk aged 5 to 19 years presented in Table 1, from 8.3 to 31.1 million people would be covered with this vaccine administration. Along those same lines, PCV13 has a greater coverage (62.9%) immunizing from 10.9 to 40.6 million of individuals. PCV13 is the only conjugate vaccine that includes serotypes 3, 6A and 19A, and in most countries this vaccine replaced the PCV7/10. Although not all of these serotypes are known to cause invasive disease exclusively, serotypes contained in PCV10 and the additional serotypes contained in PVC13 are major causes of IPD and acute otitis media.
      However, it should be noted that Table 2 presents the population potentially covered by each conjugate vaccine in LA. This information does not take into account, the vaccine efficacy, among covered serotypes, in preventing cases. Thus, Table 2 considers a supposed 100% efficacy for serotypes covered by each vaccine.
      The broadest coverage provided by PCV13 means, in practical terms, higher probability to prevent IPD cases, favoring not only children and adolescents with risk factors, but the entire population. The wider coverage of PCV13 reaffirms its superiority versus conjugate vaccines with less serotypes. Nevertheless, vaccine efficacy especially in patients with risk factors for IPD is not ensured. It is known that patients with diseases and risk factors have a lower response to vaccination.
      • Klugman K.P.
      • Madhi S.A.
      • Huebner R.E.
      • Kohberger R.
      • Mbelle N.
      • Pierce N.
      A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.
      • Adamkiewicz T.V.
      • Silk B.J.
      • Howgate J.
      • Baughman W.
      • Strayhorn G.
      • Sullivan K.
      • et al.
      Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life.
      Because of this, Table 3 presents efficacy data for risk groups obtained in clinical trials. This data indicates that, despite the lower efficacy for this particular group, a large population could be benefited.
      On the other hand, despite PCV13's protection against IPD, some studies indicate that IPD incidence by serotypes not included in the vaccine has increased up to 140%.
      • Browall S.
      • Backhaus E.
      • Naucler P.
      • Galanis I.
      • Sjöström K.
      • Karlsson D.
      • et al.
      Clinical manifestations of invasive pneumococcal disease by vaccine and non-vaccine types.
      • Iroh Tam P.Y.
      • Madoff L.C.
      • Coombes B.
      • Pelton S.I.
      Invasive pneumococcal disease after implementation of 13-valent conjugate vaccine.
      Thus, PCV13 should be seen only as part of the solution for IPD in LA. In addition, the combination of several risk factors is extremely important, and is present in many patients with an even greater risk of pneumococcal infection.
      The introduction of PCV13 as well as PPSV23 was recently recommended by ACIP in population aged 6 to 18 years under such conditions. This recommendation calls for the use of vaccines in children and adolescents in some situations of higher risk for invasive pneumococcal infections such as cerebrospinal fluid leak and cochlear implants, hemoglobinopathies, congenital or acquired immunodeficiency, cancer, renal failure, and others.

      Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP) [Internet]. Morbidity and Mortality Weekly Report, 2012 [cited 2014 Sep 13]. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6140a4.htm.

      Currently, the minimum interval for vaccination with PPSV23 after PCV13 use is 8 weeks in subjects aged up to 65 years. Although PCV13 is approved in many Latin American countries for individuals above 50 years of age, the official schedule recommendations only include the age group above 65 years (in Brazil, over 60 years old). In such conditions, the recommended vaccine should be PCV13. If the patient has more than 65 years, a PPSV23 dose is recommended with a minimum interval of 6-12 months after PCV13. In adults over 65 years and PCV13-naive previously vaccinated with PPSV23, a dose of PCV13 should be administered at least 1 year after the latest PPSV23 vaccine. If a new dose of PPSV23 is indicated (in individuals with some persistent risk factors), the interval must be of at least 5 years since the last dose of PPSV23. This recommendation will be reviewed in 2018 by the ACIP and CDC.

      Tomczyk S, Bennett N, Stoecker C, Gierke R, Moore M, Whitney C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged> 65 years: recommendations of the Advisory Commitee on Immunization Practices (ACIP) [Internet]. Morbidity and Mortality Weekly Report, 2014 [cited 2014 Dec 15]. p. 822–5. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6337a4.htm.

      4.6 Strengths and limitations

      This study should be interpreted taking into account that the availability of different data in literature contributes to a possible under/overestimated number of susceptible individuals. Also, there are several factors that may increase a child's risk of IPD, but it was not considered a possible association of two or more factors, in which an individual could be included in more than one group evaluated. Thus, the number of children or adolescents at risk may be overestimated.
      The demonstrated calculations do not consider that in some LA countries vaccination of children up to two years is occurring systematically, such as Argentina, Brazil, Uruguay and others. Thus, results were overestimated especially among those countries.
      However, a positive highlight is the use of the entire population in LA, because these countries present comparable epidemiological profiles regarding IPD incidence and prevalence. The target population of this research is also a positive highlight (children and adolescents with risk factors to develop IPD), considering they are frequently vulnerable and often neglected in studies of IPD prevention in LA.

      5. Conclusion

      Despite the stated limitations, vaccinating against IPD in children and adolescents with risk factors against IPD represents a major opportunity in this specific population. Public policies favoring IPD vaccination should be encouraged in LA by international protocols. This incentive would decrease mortality in adolescents and especially among children, supporting the reduction of child mortality - one of the millennium goals proposed by WHO.

      World Health Organization (WHO). Millennium Development Goals (MDGs). Health Topics. 2014.

      Supporting Information: Table S1. Data used in the calculation of prevalence of IPD in different high-risk groups and vaccine efficacy in these groups.
      Conflict of interest statement: Luiza Helena Falleiros Arlant has received travel or honorarium support for participation as a speaker, in external expert committees or advisory boards for MSD, Sanofi Pasteur, Pfizer, GlaxoSmithKline and Novartis. Currently, she is the co-coordinator of GREEN (Regional Study Group Pneumococcal Disease).
      Maria Luisa Avila-Aguero has worked as a speaker for Pfizer, Sanofi Pasteur, MSD and Novartis. She was member of the Advisory Board of GlaxoSmithKline, Pfizer, and MSD. Currently, she is the coordinator of GREEN (Regional Study Group Pneumococcal Disease) which is part of SLIPE (Latin American Society for Pediatric Infectious Diseases).
      María Catalina Pírez has received travel or honorarium support for participation in external expert committees or advisory boards for Merck Sharp & Dohme, Sanofi Pasteur, Pfizer, GlaxoSmithKline, Novartis and Instituto Sabin, has received honorarium support for consulting for Amsud Pasteur Foundation/Banco interamericano de Desarrollo and has received speaker honoraria for presentations for Pfizer.
      Jose Brea has received speaker honoraria for presentations for Pfizer, Sanofi-Pasteur, GSK, Novartis, MSD and participaded in advisory boards for Pfizer, Sanofi-Pasteur, GSK.
      Cristina Mariño has received travel or honorarium support for participation in external expert committees or advisory boards for Merck Sharp & Dohme, Sanofi Pasteur, Pfizer, GlaxoSmithKline and Novartis. The other authors have declared that no competing interests exist.

      Acknowledgments

      We thank Laura Haas (SENSE Company, Brazil) for editorial support in developing drafts of this manuscript. The authors were responsible for critical revisions of the manuscript for important intellectual content.

      References

        • Valenzuela M.T.
        • O’Loughlin R.
        • De La Hoz F.
        • Gomez E.
        • Constenla D.
        • Sinha A.
        • et al.
        The burden of pneumococcal disease among Latin American and Caribbean children: review of the evidence.
        Rev Panam Salud. Publica. 2009; 25: 270-279
        • Gentile A.
        • Bardach A.
        • Ciapponi A.
        • Garcia-Marti S.
        • Aruj P.
        • Glujovsky D.
        • et al.
        Epidemiology of community-acquired pneumonia in children of Latin America and the Caribbean: a systematic review and meta-analysis.
        Int J Infect Dis. 2012; 16: e5-e15
        • Buzzo A.R.
        • Roberts C.
        • Mollinedo L.G.
        • Quevedo J.M.
        • Casas G.L.
        • Soldevilla J.M.
        Morbidity and mortality of pneumonia in adults in six Latin American countries.
        Int J Infect Dis. 2013; 17: e673-e677
        • Centers for Disease Control and Prevention (CDC)
        Pneumococcal disease.
        in: Atkinson W. Hamborsky J. Wolfe S. Epidemiology and Prevention of Vaccine-Preventable Diseases.12th ed. 2012: 233-248
        • Ciapponi A.
        • Elorriaga N.
        • Rojas J.I.
        • Romano M.
        • Martí S.G.
        • Bardach A.
        • et al.
        Epidemiology of pediatric pneumococcal meningitis bacteremia in Latin America and the Caribbean: a systematic review meta-analysis.
        Pediatr Infect Dis J. 2014; 33: 971-978
        • Mitchell R.
        • Trück J.
        • Pollard A.J.
        Use of the 13-valent pneumococcal conjugate vaccine in children and adolescents aged 6-17 years.
        Expert Opin Biol Ther. 2013; 13: 1451-1465
      1. Centers for Disease Control and Prevention, (CDC). Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children – Advisory Committee on Immunization Practices (ACIP) [Internet]. Morbidity and Mortality Weekly Report, 2010 [cited 2014 Sep 13]. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5909a2.htm.

        • Pelton S.
        • Weycker D.
        • Farkouh R.
        • Strutton D.
        • Shea K.
        • Edelsberg J.
        Risk of pneumococcal disease in children with chronic medical conditions in the era of pneumococcal conjugate vaccine.
        Clin Infect Dis. 2014; 59: 615-623
        • Muhammad R.D.
        • Oza-Frank R.
        • Zell E.
        • Link-Gelles R.
        • Narayan K.M.V.
        • Schaffner W.
        • et al.
        Epidemiology of invasive pneumococcal disease among high-risk adults since the introduction of pneumococcal conjugate vaccine for children.
        Clin Infect Dis. 2013; 56: e59-e67
        • Talbot T.R.
        • Hartert T.V.
        • Mitchel E.
        • Halasa N.B.
        • Arbogast P.G.
        • Poehling K.A.
        • et al.
        Asthma as a risk factor for invasive pneumococcal disease.
        N Engl J Med. 2005; 352: 2082-2090
        • Flory J.H.
        • Joffe M.
        • Fishman N.O.
        • Edelstein P.H.
        • Metlay J.P.
        Socioeconomic risk factors for bacteraemic pneumococcal pneumonia in adults.
        Epidemiol Infect. 2009; 137: 717-726
      2. United States Renal Data System. U.S. Renal Data System 2009 Annual Data Report: Atlas of chronic kidney disease and end-stage renal disease in the United States. 2009.

        • Yin Z.
        • Rice B.D.
        • Waight P.
        • Miller E.
        • George R.
        • Brown A.E.
        • et al.
        Invasive pneumococcal disease among HIV-positive individuals 2000-2009.
        AIDS. 2012; 26: 87-94
        • Payne A.B.
        • Link-Gelles R.
        • Azonobi I.
        • Hooper W.C.
        • Beall B.W.
        • Jorgensen J.H.
        • et al.
        Invasive pneumococcal disease among children with and without sickle cell disease in the United States, 1998 to 2009.
        Pediatr Infect Dis J. 2013; 32: 1308-1312
        • Van Hoek A.J.
        • Andrews N.
        • Waight P.
        • Stowe J.
        • Gates P.
        • George R.
        • et al.
        The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England.
        J Infect. 2012; 65: 17-24
        • Smith S.A.
        • Poland G.A.
        Use of influenza and pneumococcal vaccines in people with diabetes.
        Diabetes Care. 2000; 23: 95-108
      3. CELADE – División de Población de la CEPAL. Estimaciones y proyecciones de población a largo plazo. 1950-2100 – Revisión 2013. 2013.

        • Chong Neto H.J.
        • Rosário N.A.
        • Solé D.
        Asthma and rhinitis in South America: how different they are from other parts of the world.
        Allergy, Asthma Immunol Res. 2012; 4: 62
        • Sesso R.C.
        • Lopes A.A.
        • Thomé F.S.
        • Lugon J.R.
        • Watanabe Y.
        • Santos D.R.
        Report of the Brazilian chronic dialysis census.
        J Bras Nefrol. 2012; 36: 48-53
        • Aschner P.
        Diabetes trends in Latin America.
        Diabetes Metab Res Rev. 2002; 18: S27-S31
        • Lervolino L.G.
        • Baldin P.E.A.
        • Picado S.M.
        • Calil K.B.
        • Viel A.A.
        • Campos L.A.F.
        Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies.
        Rev Bras Hematol Hemoter. 2011; 33: 49-54
      4. World Health Organization (WHO). Adult HIV prevalence (15–49 years), 2012 by WHO region [Internet]. 2012. Available from: http://www.who.int/gho/hiv/epidemic_status/prevalence/en/.

      5. Organización Panamericana de la Salud. Informe Regional de SIREVA II, 2012: datos por país y por grupos de edad sobre las características de los aislamientos de Streptococcus pneumoniae, Haemophilus influenzae y Neisseria meningitidis, en procesos invasores. Washington, DC: OPAS; 2013.

        • Klugman K.P.
        • Madhi S.A.
        • Huebner R.E.
        • Kohberger R.
        • Mbelle N.
        • Pierce N.
        A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.
        N Eng J Med. 2003; 349: 1341-1348
        • Adamkiewicz T.V.
        • Silk B.J.
        • Howgate J.
        • Baughman W.
        • Strayhorn G.
        • Sullivan K.
        • et al.
        Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life.
        Pediatrics. 2008; 121: 562-569
        • Murray C.J.L.
        • Ortblad K.F.
        • Guinovart C.
        • Lim S.S.
        • Wolock T.M.
        • Roberts D.A.
        • et al.
        Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2014; 384: 1005-1070
        • Eskola J.
        • Kilpi T.
        • Palmu A.
        • Jokinen J.
        • Haapakoski J.
        • Herva E.
        • et al.
        Efficacy of a pneumococcal conjugate vaccine against acute otitis media.
        N Eng J Med. 2001; 344: 403-409
      6. Centers for Disease Control and Prevention (CDC). Progress in introduction of pneumococcal conjugate vaccine – worldwide, 2000–2012 [Internet]. Morbidity and Mortality Weekly Report, 2013 [cited 2014 Sep 13]. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6216a4.htm?s_cid=mm6216a4_e.

      7. Pan American Health Organization (PAHO). Technical Advisory Group on vaccine - preventable diseases – final report. TAG Meeting. Buenos Aires; 2011. p. 49.

      8. República Dominicana. Incluyen vacuna contra neumococo al programa ampliado de inmunización [Internet]. Ministerio de Salud Publica. 2014 [cited 2014 Sep 13]. Available from: http://www.msp.gob.do/article/incluyen-vacuna-contra-neumococo-al-programa-ampliado-de-inmunizacion.

      9. República Bolivariana da Venezuela. Vacuna contra el neumococo reducirá la mortalidad infantil en Venezuela [Internet]. Ministerio del Poder Popular para la Comunicación y la Información. 2014 [cited 2014 Sep 13]. Available from: http://www.minci.gob.ve/2014/07/vacuna-contra-el-neumococo-reducira-la-mortalidad-infantil-en-venezuela/.

      10. Estado Plurinacional da Bolívia. Gobierno presenta vacuna “neumococos” [Internet]. 2014 [cited 2014 Sep 13]. Available from: http://www.bolivia.com/vida-sana/salud/sdi/80475/gobierno-presenta-vacuna-neumococos.

        • Ministério da Saúde (Brasil). Secretaria de Vigilância em Saúde
        Departamento de Vigilância Epidemiológica. Coordenação-Geral do Programa Nacional de Imunizações. Proposta para introdução da vacina pneumocócica 10-valente (conjugada) no calendário básico de vacinação da criança.
        Ministério da Saúde, Brasilia2010: 18
        • World Health Organization (WHO)
        Pneumococcal conjugate vaccine for childhood immunization - WHO position paper.
        Wkly Epidemiol Rec. 2007; : 93-104
        • Browall S.
        • Backhaus E.
        • Naucler P.
        • Galanis I.
        • Sjöström K.
        • Karlsson D.
        • et al.
        Clinical manifestations of invasive pneumococcal disease by vaccine and non-vaccine types.
        Eur Respir. J. 2014; 44: 1646-1657
        • Iroh Tam P.Y.
        • Madoff L.C.
        • Coombes B.
        • Pelton S.I.
        Invasive pneumococcal disease after implementation of 13-valent conjugate vaccine.
        Pediatrics. 2014; 134: 210-217
      11. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP) [Internet]. Morbidity and Mortality Weekly Report, 2012 [cited 2014 Sep 13]. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6140a4.htm.

      12. Tomczyk S, Bennett N, Stoecker C, Gierke R, Moore M, Whitney C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged> 65 years: recommendations of the Advisory Commitee on Immunization Practices (ACIP) [Internet]. Morbidity and Mortality Weekly Report, 2014 [cited 2014 Dec 15]. p. 822–5. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6337a4.htm.

      13. World Health Organization (WHO). Millennium Development Goals (MDGs). Health Topics. 2014.