Pneomococcal vaccine effectiveness in the elderly. Systematic review and meta-analysis

array:21 ["pii" => "13037691" "issn" => "02126567" "estado" => "S300" "fechaPublicacion" => "2002-09-30" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Aten Primaria. 2002;30:269-82" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3894 "formatos" => array:3 [ "EPUB" => 61 "HTML" => 3229 "PDF" => 604 ] ] "Traduccion" => array:1 [ "es" => array:16 [ "pii" => "13037447" "issn" => "02126567" "estado" => "S300" "fechaPublicacion" => "2002-09-30" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Aten Primaria. 2002;30:269-82" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 8651 "formatos" => array:3 [ "EPUB" => 55 "HTML" => 6419 "PDF" => 2177 ] ] "es" => array:11 [ "idiomaDefecto" => true "titulo" => "Efectividad de la vacuna frente al neumococo en el anciano. Revisión sistemática y metaanálisis" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "269" "paginaFinal" => "282" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Pneomococcal vaccine effectiveness in the elderly. Systematic review and meta-analysis" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J Puig-Barberà, A Belenguer Varea, M Goterris Pinto, MJ Brines Benlliure" "autores" => array:4 [ 0 => array:2 [ "Iniciales" => "J" "apellidos" => "Puig-Barberà" ] 1 => array:2 [ "Iniciales" => "A" "apellidos" => "Belenguer Varea" ] 2 => array:2 [ "Iniciales" => "M" "apellidos" => "Goterris Pinto" ] 3 => array:2 [ "Iniciales" => "MJ" "apellidos" => "Brines Benlliure" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:8 [ "pii" => "13037691" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037691?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037447?idApp=UINPBA00004N" "url" => "/02126567/0000003000000005/v0_201607121036/13037447/v0_201607121036/es/main.assets" ] ] "itemSiguiente" => array:16 [ "pii" => "13037692" "issn" => "02126567" "estado" => "S300" "fechaPublicacion" => "2002-09-30" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Aten Primaria. 2002;30:283" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1816 "formatos" => array:3 [ "EPUB" => 62 "HTML" => 1445 "PDF" => 309 ] ] "en" => array:9 [ "idiomaDefecto" => true "titulo" => "Commentary: Pneumococcal disease: is prevention possible?" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:1 [ "paginaInicial" => "283" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Comentario: Enfermedad neumocócica: ¿es posible la prevención?" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "MJ Álvarez Pasquín, JJ Gómez Marco" "autores" => array:2 [ 0 => array:2 [ "Iniciales" => "MJ" "apellidos" => "Álvarez Pasquín" ] 1 => array:2 [ "Iniciales" => "JJ" "apellidos" => "Gómez Marco" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:8 [ "pii" => "13037449" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037449?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037692?idApp=UINPBA00004N" "url" => "/02126567/0000003000000005/v0_201607121036/13037692/v0_201607121036/en/main.assets" ] "itemAnterior" => array:16 [ "pii" => "13037447" "issn" => "02126567" "estado" => "S300" "fechaPublicacion" => "2002-09-30" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Aten Primaria. 2002;30:269-82" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 8651 "formatos" => array:3 [ "EPUB" => 55 "HTML" => 6419 "PDF" => 2177 ] ] "es" => array:11 [ "idiomaDefecto" => true "titulo" => "Efectividad de la vacuna frente al neumococo en el anciano. Revisión sistemática y metaanálisis" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "269" "paginaFinal" => "282" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Pneomococcal vaccine effectiveness in the elderly. Systematic review and meta-analysis" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J Puig-Barberà, A Belenguer Varea, M Goterris Pinto, MJ Brines Benlliure" "autores" => array:4 [ 0 => array:2 [ "Iniciales" => "J" "apellidos" => "Puig-Barberà" ] 1 => array:2 [ "Iniciales" => "A" "apellidos" => "Belenguer Varea" ] 2 => array:2 [ "Iniciales" => "M" "apellidos" => "Goterris Pinto" ] 3 => array:2 [ "Iniciales" => "MJ" "apellidos" => "Brines Benlliure" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:8 [ "pii" => "13037691" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037691?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037447?idApp=UINPBA00004N" "url" => "/02126567/0000003000000005/v0_201607121036/13037447/v0_201607121036/es/main.assets" ] "asociados" => array:1 [ 0 => array:16 [ "pii" => "13037692" "issn" => "02126567" "estado" => "S300" "fechaPublicacion" => "2002-09-30" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Aten Primaria. 2002;30:283" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1816 "formatos" => array:3 [ "EPUB" => 62 "HTML" => 1445 "PDF" => 309 ] ] "en" => array:9 [ "idiomaDefecto" => true "titulo" => "Commentary: Pneumococcal disease: is prevention possible?" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:1 [ "paginaInicial" => "283" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Comentario: Enfermedad neumocócica: ¿es posible la prevención?" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "MJ Álvarez Pasquín, JJ Gómez Marco" "autores" => array:2 [ 0 => array:2 [ "Iniciales" => "MJ" "apellidos" => "Álvarez Pasquín" ] 1 => array:2 [ "Iniciales" => "JJ" "apellidos" => "Gómez Marco" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:8 [ "pii" => "13037449" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037449?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037692?idApp=UINPBA00004N" "url" => "/02126567/0000003000000005/v0_201607121036/13037692/v0_201607121036/en/main.assets" ] ] "en" => array:14 [ "idiomaDefecto" => true "titulo" => "Pneomococcal vaccine effectiveness in the elderly. Systematic review and meta-analysis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "269" "paginaFinal" => "282" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "J Puig-Barberà, A Belenguer Varea, M Goterris Pinto, MJ Brines Benlliure" "autores" => array:4 [ 0 => array:3 [ "Iniciales" => "J" "apellidos" => "Puig-Barberà" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "Iniciales" => "A" "apellidos" => "Belenguer Varea" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 2 => array:3 [ "Iniciales" => "M" "apellidos" => "Goterris Pinto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 3 => array:3 [ "Iniciales" => "MJ" "apellidos" => "Brines Benlliure" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Health Promotion, Castellón Public Health Center, Castellón, Spain. Working Group on Vaccines, Valencian Society of Family and Community Medicine (SVMFYC). Spain." "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Geriatrics Unit, Internal Medicine Service, Hospital de la Rivera, Alzira, Valencia, Spain." "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Burriana Health Center, Burriana, Castellón, Spain." "etiqueta" => "c" "identificador" => "affc" ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Efectividad de la vacuna frente al neomococo en el anciano. Revisión sistemática y metaanalisis" ] ] "textoCompleto" => "Introduction<hr></hr>The indications for pneumococcal vaccination in persons aged 65 years or more are controversial because of discordant results between different studies,1-4 and important differences have been noted in international recommendations for vaccination in this age group.2,5,6 The controversy first appeared at the beginning of the 1980s in the light of difficulties large clinical trials had in demonstrating the effectiveness of vaccination in older persons,7 and it was argued that the large numbers of participants required to guarantee sufficient statistical power to prove the protective efficacy of vaccination made such clinical trials impracticable.8 At the end of the 1980s, recommendations for vaccination in persons older than 65 years were based on the results of observational studies. It is therefore high time for a systematic, thorough review of the literature, which now includes clinical trials and observational studies. Methodological quality criteria can now be used to guarantee an unbiased estimate of the effectiveness of pneumococcal vaccination in older persons.<hr></hr>Methodology<hr></hr><img src="27v30n05-13037691tab01.gif"></img>To estimate the effectiveness of 23-valent pneumococcal capsular polysaccharide vaccination in preventing the disease caused by pneumococcal organisms in persons older than 65 years, we systematically reviewed the literature, with attention to both clinical trials and observational studies. Bibliographic databases were searched for articles published in Spanish, English or French between the years 1964 and 2000 in MEDLINE, and between 1988 and 2000 in EMBASE. The CD-ROM edition of the Cochrane Library database9 was searched up to and including the first disk issued in 2001. Previously unidentified items were searched for in the reference lists of retrieved articles and in those of four separate reviews (three of which were systematic) of the effectiveness of polysaccharide vaccines.1-4 Researchers were contacted to request unpublished information and other unidentified items.Two search strategies were used: the sensitive strategy was based on the terms pneumoc* AND vaccin* AND elderly, and the specific strategy used the terms pneumoc* AND vaccin* AND elderly AND (effectiv* OR effica*). We retrieved clinical trials, cohort studies and case-control studies that reported results for the effect of vaccination on the risk of pneumococcal disease, defined as pneumococcal pneumonia or invasive disease caused by pneumococci of the serotypes included in the vaccine and identified by culture, in populations of adults aged 65 years or older. Invasive disease was defined by the isolation of pneumococcal organisms from a normally sterile anatomical site. 12.Inclusion, exclusion and evaluation criteria for studiesStudies were evaluated independently by four researchers on the basis of predefined criteria for validity.10-13 Differences were resolved by consensus between the researchers. The inclusion criteria used to select studies were: a) information included on the administration of the vaccine in adults aged 65 years or more; b) risk measured for pneumonia or invasive disease caused by pneumococci belonging to the serotypes included in the vaccine; c) information included on the comparability of cases and controls or exposed and unexposed persons, ie, information that both of the groups being compared belonged to the same study base;14d) random allocation according to an adequately concealed double-blind procedure in clinical trials;15e) response rates higher than 80% for observational studies, or drop-out rates lower than 10% for clinical trials;16f) absence of classification bias or serious violations of blinding;15g) suitable control of confounding variables, and h) sufficient information to be able to repeat the analysis.17 Noncompliance with either of the first two criteria (a or b) led to exclusion of the study. The other criteria were used as parameters to evaluate the quality of the studies, which were classified according to the following matrix:12<img src="27v30n05-13037691tab02.gif"></img>We excluded from the quantitative analysis all studies classified as C, and included all those classified as A or B.AnalysisA descriptive analysis was prepared based on the year of publication, age groups included, type of population, study design, number of serotypes included in the vaccine, type of results studied and number of participants; relative risks (RR) were estimated and their confidence intervals (CI) calculated. Because of the low frequency of the events of interest, the odds ratio was considered an unbiased estimator of the RR. For each study we recorded factors that compromised the validity of the estimates and the likelihood that the results were biased.Before estimating the protective effect of vaccination, we evaluated the homogeneity of the studies with graphs that illustrated point estimates of RR for pneumococcal disease and the CI, and their overlap or divergence. The hypothesis of homogeneity was tested by estimating the chi-squared value;18 significant heterogeneity was considered to exist when P<.10. The possibility of publication bias was explored with the test of Egger et al.19 The degree to which heterogeneity of the estimates was influenced by study characteristics such as design, number of serotypes in the vaccine, year and biases was studied by regression (metaregression analysis) of these characteristics on the logarithm of RR.20 Only when the inclusion and validity criteria were satisfied and homogeneity could not be ruled out did we estimate the aggregate RR and its CI with the random effects method of DerSimonian and Laird18 for a 95% confidence interval. When the confidence interval of the estimated RR included 1, we interpreted this to mean that vaccination did not confer significant protection against pneumococcal disease. The aggregate effectiveness of vaccination was calculated as (1RR)*100.21The number needed to treat (NNT) to avoid the outcomes of interest was also calculated.22,23 All calculations were done with MS-Excel, MS-Access, Epi Info v. 6.04b and STATA v. 5 software.<hr></hr>Results <hr></hr>Twenty-five items were identified that compared the effectiveness of pneumococcal vaccination in preventing pneumococcal disease versus a control group.7,24-47 Four articles were excluded because they dealt with young adults or Children,24,27,28,34 and a fifth item was excluded because it included individuals aged 10 years or more, did not supply information on age groups, and was done in a setting that made it difficult to extrapolate the results to western populations.26 Of the remaining 20 articles (Table 1), 11 were clinical trials7,25,29,31,33,35,36,38,44-46 and 9 were observational studies.30,32,37,39-43,47<img src="27v30n05-13037691tab03.gif"></img><img src="27v30n05-13037691tab04.gif"></img>Of the 11 clinical trials retrieved, eight analyzed the efficacy of the vaccine in preventing pneumococcal disease caused by serotypes included in the vaccine.7,25,29,31,33,35,45,46 Six studies (Table 2) had one or both of the following problems: appropriate random allocation of the participants to the experimental or control group was not used, or the allocation procedure was not adequately concealed from the researchers and participants in the treatment group.25,29,31,33,44,46 For the five remaining studies we estimated a low or moderate likelihood of bias, as participants were assigned randomly to one group or the other, and because researchers and participants were appropriately blinded to the procedure.7,35,36,38,45<img src="27v30n05-13037691tab05.gif"></img>Of the nine observational studies we retrieved, four analyzed the effectiveness of the vaccine in preventing pneumococcal disease caused by serotypes included in the vaccine,32,37,41,42 and six were judged highly likely to be biased (Table 3). The patients described in the study by Bolan et al.32 were included in the study by Butler et al.;42 the former did not provide any indication of the thoroughness of the information regarding exposure, whereas the second lacked information about exposure for 39% of the participants eligible for inclusion. We therefore considered the validity of these estimates to be insufficient. In the study by Sims et al.,39 107 participants (46%) of a total of 229 were excluded because information about exposure was missing. The two studies by Shapiro et al. published in 198430 and 199141 had characteristics that met the criteria for estimates of moderate validity, and also presented estimates that changed direction when the analysis was repeated after ignoring the case-control matching30 or after information for 122 participants vaccinated with the 23-valent capsule polysaccharide vaccine was excluded.41 The study by Gable et al.40 was based on administrative data, and the analysis was inadequate. Lastly, in the study by Nichols et al.47 exposed (vaccinated) and unexposed (unvaccinated) individuals could not be considered members of the same population at risk.<img src="27v30n05-13037691tab06.gif"></img>Effect of vaccination on pneumococcal pneumonia caused by serotypes included in the vaccineEight of the clinical trials retrieved (Table 1, Figure 1a) estimated the RR of pneumococcal pneumonia in vaccinated versus unvaccinated persons.7,25,29,31,35,36,45,46 Three studies36,45,46 did not estimate the number of cases of pneumococcal pneumonia caused by serotypes included in the vaccine (Table 2). Only the study by Kaufman et al.,25 who investigated a vaccine composed of three capsular serotypes (Table 1), reported a favorable estimate of the vaccine´s protective efficacy. As shown in Figures 1a and 1b, this study cannot be considered similar to the others carried out between 1980 and 1998. None of the other clinical trials found a clinically significant protective effect (RR) for vaccination (Figure 1b). Figure 1c shows the estimates from those three trials (from among the original eight studies) that fulfilled the criteria for validity of the estimates (Table 2). The trial published by Austrian et al.7 was excluded because samples for the identification of the serotype that caused pneumonia were obtained from fewer than 75% of the patients, althoughas shown in Figure 1 and Table 1none of their estimates showed vaccination to be protective. Lastly, only the clinical trial reported by Simberkoff et al.35 in 1986 fulfilled the inclusion criteria for validity of the estimates and for our definition of a case: these authors provided estimates of the risk of pneumococcal pneumonia according to each serotype included in the vaccine.<img src="27v30n05-13037691tab07.gif"></img>Figure 1. Relative risks of pneumococcal pneumonia. Part a shows all studies that measured the effectiveness of vaccination in preventing this disease; the test for homogeneity yielded a chi-squared value of 191.63 with 7 degrees of freedom and P<.001. Part b shows that after the study by Kaufman et al.25 was excluded, the test for homogeneity yielded a chi-squared value of 2.69 with 7 degrees of freedom and P<.85. Part c shows the three studies that calculated the RR for pneumococcal pneumonia in vaccinated versus unvaccinated persons and that fulfilled our methodological quality criteria. However, two studies (Davis et al.36 and Ortqvist et al.45) failed to investigate the serotypes that caused the disease. The areas of the boxes reflect the precision of the estimates obtained in different studies.The best available estimate placed the RR for pneumococcal pneumonia in vaccinated individuals compared to unvaccinated individuals at 0.86, with a 95% CI of 0.24 to 2.99. Effectiveness in preventing pneumococcal pneumonia caused by the serotypes in the vaccine was 14%, with a 95% CI of 199% to 76%. The number of individual needed to vaccinate (NNT) to prevent one case was 1197. The CI indicated the possibility that one case of pneumococcal pneumonia could be caused for every 85 or more persons vaccinated, and that one case could be prevented for every 242 or more persons vaccinated; this CI also included zero Table 4).<img src="27v30n05-13037691tab08.gif"></img>Effect of vaccination on invasive disease caused by serotypes included in the vaccineTen studied provided estimates of the effectiveness of vaccination against invasive disease caused by serotypes included in the vaccine (Figure 2a). Only three studies (Kaufman et al.,25 Bolan et al.32 and Butler et al.42) concluded that vaccination was significantly superior to the placebo (Figure 2a). The study by Kaufman et al.25 had important limitations regarding random allocation of the participants and blinding of the investigators; the studies by Bolan et al.32 and Butler et al.42 reported results for the same series of patients and did not provide information on exposure for a large percentage of participants. The studies by Bentley et al.,29 Klastersky et al.33 and Honkanen et al.46 did not satisfy the criteria because of problems with random allocation of the participants to different interventions, or problems with blinding the investigators or the participants (Table 2).<img src="27v30n05-13037691tab09.gif"></img>Figure 2. a) Estimates of relative risk (RR) of invasive disease caused by the pneumococcal serotypes included in the vaccine and the 95% confidence intervals (95% CI). For all studies retrieved, the test for homogeneity yielded a chi-squared value of 16.12 with 9 degrees of freedom and P=.06. The x axis scale has been truncated on both ends to improve legibility. b) Estimates of RR and 95% CI for the studies that fulfilled our inclusion criteria. Global RR was 0.68, 95% CI was 0.39 to 1.18; P=.17. The test for homogeneity yielded a chi-squared value of 2.09 with 3 degrees of freedom and P=.55. The areas of the boxes reflect the precision of the estimates obtained in different studies.Of the 10 studies we examined, the clinical trials by Simberkoff et al.35 and Ortqvist et al.,45 and the observational studies by Forrester et al.37 and Shapiro et al.41 fulfilled our methodological quality criteria well enough so that we could trust the validity of their results (Tables 2 and 3). The aggregate RR for invasive disease was 0.68, with a 95% CI of 0.39 to 1.18 and a P=.17 (Figure 2b). The chi-squared test used to check the hypothesis of homogeneity of the different studies yielded a value of 2.09 with 3 degrees of freedom and a P=.55. The test of Egger et al. used to determine the possibility of publication bias yielded a nonsignificant value of P=.79. Effectiveness of vaccination was 32%, with a 95% CI of 18% to 51%, a result that implied that vaccination had no significant effect.The estimated number of individuals needed to vaccinate (NNT) to prevent one case of invasive disease was 785, with a CI that showed that one case of invasive disease might be caused for every 1399 or more persons vaccinated, and that one case might be prevented for every 412 persons or more vaccinated. The CI again included zero (Table 4).Sensitivity analysisFigure 1a illustrates the effectiveness of vaccination in preventing pneumococcal pneumonia according to different studies. The results of the study by Kaufman et al.25 explained the heterogeneity in the estimates of risk for pneumococcal pneumonia; this was further confirmed by metaregression analysis, which showed no significant alterations in the results according to the number of serotypes included in the vaccine, the year the study was done, or publication bias after the Kaufman et al. study was excluded.Figure 2a shows that the results of studies that investigated the effectiveness of the vaccine in preventing invasive disease were markedly heterogeneous. Metaregression on the logarithm of RR and analysis of the influence of the year of the study, the study design, the serotypes included in the vaccine or publication bias showed that this last factor was the one that best explained (P=.009) the variability in our results (Figure 3). In fact, the point estimate of effectiveness of the vaccination was 2.6-fold greater in studies for which we considered validity of the estimates to be compromised than in studies we considered free from bias (classified as A or B). The RR increased from 0.26 to 0.68, and the CI for the latter value indicated that the effect of vaccination was null.<img src="27v30n05-13037691tab10.gif"></img>Figura 3. Results of metaregression analysis of the effect of publication bias on estimates of the effectiveness of vaccination in preventing invasive disease. Estimates for studies classified as A or B were significantly different (P=.004) from estimates obtained for studies classified as C. Interpretation of values along the x axis: A, A Low likelihood of bias; B, moderate likelihood of bias; C, high likelihood of bias (see Methods section).<hr></hr>Discussion <hr></hr><img src="27v30n05-13037691tab11.gif"></img>Twenty-five years after vaccination with capsular polysaccharide vaccines for pneumococci was first authorized, uncertainty remains as to their effectiveness, and some authors have warned that recommendations in favor of systematic vaccination for all persons aged 65 years or more need to be reviewed in the light of current knowledge.4 This situation has been fomented by proponents of vaccination who claimed that clinical trials would be impracticable and that observational studies were sufficient.8 The present sytematic review of the literature and meta-analysis included both observational studies and clinical trials, and obtained estimates of the effectiveness of vaccination in which the lower limit of the CI was a negative value. In other words, we found no proof of the effectiveness of pneumococcal vaccine in reducing or preventing pneumococcal disease in older persons. These results are in agreement with the findings of Fine et al.1 and Moore et al.,4 who included in their reviews only clinical assays.Several factors may compromise the results of a systematic review of the literature.19 One possible source of bias is that studies eligible for inclusion may be overlooked because the predominance of publications in English makes studies in other languages less likely to be cited and retrieved. Another possible bias arises from the fact that the databases we used for our literature searches are selective in the references they include. Moreover, unpublished studiesmost of which report negative findingsare not retrieved. In the present study we did not limit our searches to studies in English. We searched MEDLINE, EMBASE and the Cochrane Library, and made appropriate efforts to retrieve unpublished studies such as those by Austrian et al.,7 a clinical trial with adequately concealed random allocation, double-blinding and a large number of participants (13 600). We contacted other researchers to obtain information on additional publications and scrutinized the reference lists of the items retrieved from database searches. In fact, the results of the test of Eggar et al., which we applied to studies that investigated invasive disease, supported our assumption that no bias was introduced by the noninclusion of studies that might have been overlooked.19Another source of error is bias in the choice and application of inclusion and exclusion criteria, data extraction and quality control criteria. To avoid these pitfalls the aims and inclusion criteria were defined before the study was begun.12 Moreover, we included both clinical trials and observational studies. All items were reviewed and assessed independently by the authors, who all used the same methods of analysis.With regard to the studies we included, possible sources of heterogeneity were reduced by adapting our selection process to the question that formed the basis of the present analysis. The use of age as an inclusion criterion led us to exclude studies of children or young adults, in whom the response to vaccination differs from that in older persons;1 in addition, we opted to include only those studies with unambiguous clinical outcomes that evaluated the protection conferred against pneumococcal pneumonia or invasive disease caused by S. pneumonia serotypes included in the vaccine.A further potential source of heterogeneity between studies included in our analysis is the aggregation of results of clinical assays and observational studies. However, for studies designed and executed with adequate guarantees of methodological rigor, the results of clinical trials and observational studies concur.48,49 Heterogeneity of the findings from included and excluded studies (Figure 2a) was explained mainly by the presence or absence of factors that compromised the validity of the estimates (Figure 3), as opposed to factors such as the type of study design, year of publication or number of serotypes in the vaccine, which had no significant influence on the results.In comparison to fixed effect models, our random effects statistical model can be considered an appropriate method for aggregating data from different studies. The former approach assumes that differences in the estimates are caused only by sampling error, whereas the random effects model also takes into account the fact that because the characteristics of the participants were not homogeneous across the studies we included, the magnitude of the effects of vaccination differed between studies. This was in fact the case in the present review: the studies we retrieved involved populations that differed in their risk profiles, regardless of the participants´ age18. The discrepancy between our findings and the results of the systematic review by Hutchison et al.3 can be explained by the fact that these authors pooled the results of studies involving different age groups. When we controlled for this factor, the statistical significance of the differences in the estimates disappeared.In accordance with the terminology proposed by Altman,23 we present our results as estimates of the number needed to treat (ie, to vaccinate) and the confidence interval. We extrapolated our figures to the most plausible incidence of cases of invasive disease in the community50 50 per 100 000 persons aged 65 years or olderassuming that 90% of the cases are caused by one of the serotypes included in the vaccine. The estimated NNT to prevent one case of invasive disease is 6947, with a CI that includes, on one extreme, the chance of causing one case of invasive disease per 12 352 persons or more vaccinated, and on the other extreme, the chances of preventing one case per every 3644 or more persons vaccinated. These estimates mean that we cannot claim to have sufficient evidence to support vaccination. The actual estimate lies somewhere on a continuum of values that includes, in addition to the null effect, the possibility that vaccination itself might contribute to cases of the disease it is intended to prevent.In conclusion, our review provides no proof that pneumococcal vaccination with nonconjugate capsular polysaccharide vaccines of S. pneumoniae is effective in reducing or preventing pneumococcal disease in older persons. In the light of the results of the present review and meta-analysis, we can only conclude that the systematic recommendation for vaccination in the population of persons 65 years of age or older should not be made in the absence of results of clinical trials that unequivocally demonstrate a protective effect.<hr></hr>Acknowledgments <hr></hr>We thank Dr. Soledad Márquez Calderón of the Andalusia Public Health School, Dr. Juan B. Bellido of the Epidemiolgy Section, Castellón Public Health Center, and Dr. Vicente Palop of the Geriatrics Unit, Internal Medicine Service, Hospital de la Ribera in Alzira, Valencia, for their comments on and contributions to earlier versions of this manuscript. Correspondence: Joan Puig-Barberà. Avenida Ferrandis Salvador, 50. 12100 Castellón. España. E-mail: jpuig@terra.es Based on a talk given at the XXI Congress of the Spanish Society of Family and Community Medicine, San Sebastián, 14-17 November 2001.Awarded First prize by the PAPPS-semFYM/Almirall Prodesfarma at the XXI Congress of the Spanish Society of Family and Community Medicine.  Manuscript accepted for publication 20 February 2002." "pdfFichero" => "27v30n05a13037691pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec692960" "palabras" => array:4 [ 0 => "Metaanálisis" 1 => "Infección neumocócica" 2 => "Vacunación" 3 => "Anciano" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec692959" "palabras" => array:4 [ 0 => "Meta-analysis" 1 => "Pneumococcal infection" 2 => "Vaccination" 3 => "Aged" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "Aim. Estimate pneumococcal vaccine effectiveness in preventing Streptococcus pneumoniae illness in the elderly. Design. Systematic review and meta-analysis. Data source. MEDLINE, years 1964 to the 2000; EMBASE, from 1988 to the 2000; Cochrane Library, identified studies and previously published systematic reviews citations peruse, and contacts with field experts. Study selection. Clinical trials, cohort and case-control studies, published in Spanish, English or French, that estimated pneumococcal disease rates in vaccinated or not vaccinated elderly. Data extraction. The studies were valued independently by four investigators with predefined criteria of validity, such as results comparing rates of disease caused by serotypes included in the vaccine, random allocation, double blind design, included subjects pertaining to the same study base, and losses of less than 10% in clinical trials and 20% in observational studies. Results. Eight clinical trials considered the relative risk (RR) of pneumococcal pneumonia, three did not make estimations on pneumonia originated by serotypes included in the vaccine and only one study fulfilled all the inclusion criteria. Vaccinated versus not vaccinated pneumococcal pneumonia RR was 0.86 (95% CI, 0.24 to 2.99). Vaccine effectiveness was 14% (95% CI, 199 to 76%). Ten studies performed estimations on the effectiveness of the vaccine on invasive disease by vaccine serotypes. Of these, two clinical trials and two observational studies fulfilled the required quality criteria. RR of invasive disease was of 0.68 (95% CI, 0.39-1.18); vaccine effectiveness was 32% (95% CI, 1861%). Conclusions. No evidence was found supporting pneumococcal vaccine effectiveness to reduce or avoid S. pneumoniae disease in the elderly." ] "es" => array:1 [ "resumen" => "Objetivo. Estimar la efectividad de la vacuna neumocócica para evitar enfermedad por Streptococcus pneumoniae en ancianos. Diseño. Revisión sistemática y metaanálisis. Fuentes de datos. MEDLINE, años 1964 a 2000; EMBASE, de 1988 a 2000; Cochrane Library, citas bibliográficas de estudios identificados, revisiones sistemáticas anteriores y contactos con otros autores. Selección de los estudios. Ensayos clínicos, estudios de cohortes y de casos y controles, publicados en castellano, inglés o francés, que estimaron tasas de enfermedad neumocócica en ancianos vacunados y no vacunados. Extracción de datos. Los estudios fueron valorados independientemente por 4 investigadores con criterios de validez predefinidos, tales como realizar estimaciones de tasas de enfermedad por serotipos incluidos en la vacuna, asignación aleatoria, doble enmascaramiento, pertenencia a una misma base del estudio de los sujetos incluidos y tasas de pérdida inferiores al 10% en ensayos clínicos y al 20% en los estudios observacionales. Resultados. Ocho ensayos clínicos estimaron el riesgo relativo (RR) de neumonía neumocócica, tres no realizaron estimaciones sobre neumonía originada por serotipos incluidos en la vacuna y sólo uno de los 8 cumplió los criterios de inclusión. El RR de neumonía neumocócica de los vacunados, frente a los no vacunados, fue del 0,86 (intervalo de confianza [IC] del 95%, 0,24 a 2,99). La efectividad de la vacuna fue del 14% (IC del 95%, 199 al 76%). Diez estudios llevaron a cabo estimaciones de la efectividad de la vacuna sobre enfermedad invasora por serotipos incluidos en la vacuna. De éstos, dos ensayos clínicos y dos estudios observacionales reunieron los criterios de calidad requeridos. El RR de enfermedad invasora fue de 0,68 (IC del 95%, 0,39 a 1,18). La efectividad de la vacuna fue del 32% (IC del 95%, ¿18 a 61%). Conclusiones. No se encontraron pruebas de la efectividad de la vacuna neumocócica para reducir o evitar la enfermedad neumocócica en el anciano." ] ] "multimedia" => array:22 [ 0 => array:6 [ "identificador" => "tbl1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab01.gif" "imagenAlto" => 944 "imagenAncho" => 706 "imagenTamanyo" => 30881 ] ] ] ] ] ] 1 => array:6 [ "identificador" => "tbl2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab02.gif" "imagenAlto" => 202 "imagenAncho" => 353 "imagenTamanyo" => 7263 ] ] ] ] ] ] 2 => array:6 [ "identificador" => "tbl3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab03.gif" "imagenAlto" => 978 "imagenAncho" => 731 "imagenTamanyo" => 41751 ] ] ] ] ] ] 3 => array:6 [ "identificador" => "tbl4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab04.gif" "imagenAlto" => 887 "imagenAncho" => 733 "imagenTamanyo" => 43695 ] ] ] ] ] ] 4 => array:6 [ "identificador" => "tbl5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab05.gif" "imagenAlto" => 756 "imagenAncho" => 732 "imagenTamanyo" => 41057 ] ] ] ] ] ] 5 => array:6 [ "identificador" => "tbl6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab06.gif" "imagenAlto" => 730 "imagenAncho" => 735 "imagenTamanyo" => 38747 ] ] ] ] ] ] 6 => array:8 [ "identificador" => "tbl7" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab07.gif" "imagenAlto" => 215 "imagenAncho" => 729 "imagenTamanyo" => 37892 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Relative risks of pneumococcal pneumonia. Part a shows all studies that measured the effectiveness of vaccination in preventing this disease; the test for homogeneity yielded a chi-squared value of 191.63 with 7 degrees of freedom and P < .001. Part b shows that after the study by Kaufman et al.25 was excluded, the test for homogeneity yielded a chi-squared value of 2.69 with 7 degrees of freedom and P < .85. Part c shows the three studies that calculated the RR for pneumococcal pneumonia in vaccinated versus unvaccinated persons and that fulfilled our methodological quality criteria. However, two studies (Davis et al.36 and Ortqvist et al.45) failed to investigate the serotypes that caused the disease. The areas of the boxes reflect the precision of the estimates obtained in different studies." ] ] 7 => array:6 [ "identificador" => "tbl8" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab08.gif" "imagenAlto" => 237 "imagenAncho" => 725 "imagenTamanyo" => 11756 ] ] ] ] ] ] 8 => array:8 [ "identificador" => "tbl9" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab09.gif" "imagenAlto" => 373 "imagenAncho" => 730 "imagenTamanyo" => 32270 ] ] ] ] ] "descripcion" => array:1 [ "en" => "a) Estimates of relative risk (RR) of invasive disease caused by the pneumococcal serotypes included in the vaccine and the 95% confidence intervals (95% CI). For all studies retrieved, the test for homogeneity yielded a chi-squared value of 16.12 with 9 degrees of freedom and P=.06. The x axis scale has been truncated on both ends to improve legibility. b) Estimates of RR and 95% CI for the studies that fulfilled our inclusion criteria. Global RR was 0.68, 95% CI was 0.39 to 1.18; P=.17. The test for homogeneity yielded a chi-squared value of 2.09 with 3 degrees of freedom and P=.55. The areas of the boxes reflect the precision of the estimates obtained in different studies." ] ] 9 => array:8 [ "identificador" => "tbl10" "etiqueta" => "Figura 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab10.gif" "imagenAlto" => 505 "imagenAncho" => 730 "imagenTamanyo" => 41434 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Results of metaregression analysis of the effect of publication bias on estimates of the effectiveness of vaccination in preventing invasive disease. Estimates for studies classified as A or B were significantly different (P=.004) from estimates obtained for studies classified as C. Interpretation of values along the x axis: A, A Low likelihood of bias; B, moderate likelihood of bias; C, high likelihood of bias (see Methods section)." ] ] 10 => array:6 [ "identificador" => "tbl11" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "27v30n05-13037691tab11.gif" "imagenAlto" => 556 "imagenAncho" => 332 "imagenTamanyo" => 23016 ] ] ] ] ] ] 11 => array:5 [ "identificador" => "tbl12" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 12 => array:5 [ "identificador" => "tbl13" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 13 => array:5 [ "identificador" => "tbl14" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 14 => array:5 [ "identificador" => "tbl15" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 15 => array:5 [ "identificador" => "tbl16" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 16 => array:5 [ "identificador" => "tbl17" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 17 => array:5 [ "identificador" => "tbl18" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 18 => array:5 [ "identificador" => "tbl19" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 19 => array:5 [ "identificador" => "tbl20" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 20 => array:5 [ "identificador" => "tbl21" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] 21 => array:5 [ "identificador" => "tbl22" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Efficacy of pneumococcal vaccination in adults. A meta-analysis of randomized controlled trials. Arch Intern Med 1994;154:2666-77." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Efficacy of pneumococcal vaccination in adults. A meta-analysis of randomized controlled trials." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Fine MJ" 1 => "Smith MA" 2 => "Carson CA" 3 => "Meffe F" 4 => "Sankey SS" 5 => "Weissfeld LA" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "1994" "volumen" => "154" "paginaInicial" => "2666" "paginaFinal" => "77" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7993150" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997;46(RR-8):1-24." "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "CDC." ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Clinical effectiveness of pneumococcal vaccine. Meta-analysis. Can Fam Physician 1999;45:2381-93." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Clinical effectiveness of pneumococcal vaccine. Meta-analysis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Hutchison BG" 1 => "Oxman AD" 2 => "Shannon HS" 3 => "Lloyd S" 4 => "Altmayer CA" 5 => "Thomas K." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Can Fam Physician" "fecha" => "1999" "volumen" => "45" "paginaInicial" => "2381" "paginaFinal" => "93" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10540698" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Are the pneumococcal polysaccharide vaccines effective? Meta-analysis of the prospective trials. BMC Fam Pract 2000;1:1." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Are the pneumococcal polysaccharide vaccines effective? Meta-analysis of the prospective trials." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Moore RA" 1 => "Wiffen PJ" 2 => "Lipsky BA." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1471-2296-1-1" "Revista" => array:5 [ "tituloSerie" => "BMC Fam Pract" "fecha" => "2000" "volumen" => "1" "paginaInicial" => "1" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11038265" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Informe sobre la vacuna neumocócica. Med Clin (Barc) 1994;102:383-6." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Informe sobre la vacuna neumocócica." "idioma" => "es" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Subdirección General de Prestaciones y Evaluación de Tecnologías Sanitaria.s" 1 => "Ministerio de Sanidad y Consumo." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Med Clin (Barc)" "fecha" => "1994" "volumen" => "102" "paginaInicial" => "383" "paginaFinal" => "6" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Actividades preventivas en atención primaria: identificación de áreas de concordancia entre guías de práctica clínica basadas en la evidencia. Med Clin (Barc) 2000;114(Supl 2):88-92." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Actividades preventivas en atención primaria: identificación de áreas de concordancia entre guías de práctica clínica basadas en la evidencia." "idioma" => "es" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Gosalbes-Soler V" 1 => "Márquez-Calderón S" 2 => "Maiques-Galán A" 3 => "LatourPérez J" 4 => "Bernal-Delgado E" 5 => "Puig-Barberà J" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Med Clin (Barc)" "fecha" => "2000" "volumen" => "114" "paginaInicial" => "88" "paginaFinal" => "92" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Surveillance of pneumococcal infection for field trials of polyvalent pneumococcal vaccines. DAB-VDP-12-84, 1-84. 1980 [ref. type: report]. Bethesda (MD), National Institute of Health." "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Austrian R." ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Resolving the pneumococcal vaccine controversy: are there alternatives to randomized clinical trials? Rev Infect Dis 1984;6:589-600." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Resolving the pneumococcal vaccine controversy: are there alternatives to randomized clinical trials?" "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Clemens JD" 1 => "Shapiro ED." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Infect Dis" "fecha" => "1984" "volumen" => "6" "paginaInicial" => "589" "paginaFinal" => "600" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6390636" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Oxford: Update Software, 2001." "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "The Cochrane Librar.y" 1 => "Issue 1" 2 => "Updated quarterly." ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Methodology and reports of systematic reviews and meta-analyses: a comparison of Cochrane reviews with articles published in paper-based journals. JAMA 1998;280:278-80." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Methodology and reports of systematic reviews and meta-analyses: a comparison of Cochrane reviews with articles published in paper-based journals." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Jadad AR" 1 => "Cook DJ" 2 => "Jones A" 3 => "Klassen TP" 4 => "Tugwell P" 5 => "Moher M" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "1998" "volumen" => "280" "paginaInicial" => "278" "paginaFinal" => "80" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9676681" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses. Lancet 1999;354:1896-900." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Moher D" 1 => "Cook DJ" 2 => "Eastwood S" 3 => "Olkin I" 4 => "Rennie D" 5 => "Stroup DF." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1999" "volumen" => "354" "paginaInicial" => "1896" "paginaFinal" => "900" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10584742" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Cochrane Reviewers' Handbook 4.0 [updated July 1999]. The Cochrane Library [database on CDROM]. The Cochrane Collaboration. Oxford: Update Software, 2000." "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Clarke M" 1 => "Oxman AD" 2 => "editors." ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008-12." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Stroup DF" 1 => "Berlin JA" 2 => "Morton SC" 3 => "Olkin I" 4 => "Williamson GD" 5 => "Rennie D" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2000" "volumen" => "283" "paginaInicial" => "2008" "paginaFinal" => "12" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10789670" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The «case-control» study: valid selection of subjects. J Chronic Dis 1985;38:543-8." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The «case-control» study: valid selection of subjects." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Miettinen OS." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Chronic Dis" "fecha" => "1985" "volumen" => "38" "paginaInicial" => "543" "paginaFinal" => "8" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4008595" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-12." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Schulz KF" 1 => "Chalmers I" 2 => "Hayes RJ" 3 => "Altman DG." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "1995" "volumen" => "273" "paginaInicial" => "408" "paginaFinal" => "12" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7823387" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Evidence-based medicine. How to practice and teach EBM. 2nd ed. London: Churchill Livingstone, 2000." "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Sackett DL" 1 => "Strauss SE" 2 => "Richardson WS" 3 => "Rosenberg W" 4 => "Haynes RB." ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The importance of quality of primary studies in producing unbiased systematic reviews. Arch Intern Med 1996;156:661-6." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The importance of quality of primary studies in producing unbiased systematic reviews." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Khan KS" 1 => "Daya S" 2 => "Jadad A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "1996" "volumen" => "156" "paginaInicial" => "661" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8629879" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Meta-analysis in clinical trials." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "DerSimonian R" 1 => "Laird N." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Control Clin Trials" "fecha" => "1986" "volumen" => "7" "paginaInicial" => "177" "paginaFinal" => "88" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3802833" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Bias in meta-analysis detected by a simple, graphical test." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Egger M" 1 => "Davey SG" 2 => "Schneider M" 3 => "Minder C." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "BMJ" "fecha" => "1997" "volumen" => "315" "paginaInicial" => "629" "paginaFinal" => "34" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9310563" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "sbe23: meta-analysis regression. Stata Tech Bull 1998;42:16-24." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "sbe23: meta-analysis regression." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Sharp S." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Stata Tech Bull" "fecha" => "1998" "volumen" => "42" "paginaInicial" => "16" "paginaFinal" => "24" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Proportion of disease caused or prevented by a given exposure, trait or intervention. Am J Epidemiol 1974;99: 325-32." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Proportion of disease caused or prevented by a given exposure, trait or intervention." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Miettinen OS." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Epidemiol" "fecha" => "1974" "volumen" => "99" "paginaInicial" => "325" "paginaFinal" => "32" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4825599" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318:1728-33." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "An assessment of clinically useful measures of the consequences of treatment." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Laupacis A" 1 => "Sackett DL" 2 => "Roberts RS." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM198806303182605" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1988" "volumen" => "318" "paginaInicial" => "1728" "paginaFinal" => "33" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3374545" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Confidence intervals for the number needed to treat. BMJ 1998;317:1309-12." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Confidence intervals for the number needed to treat." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Altman DG." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "BMJ" "fecha" => "1998" "volumen" => "317" "paginaInicial" => "1309" "paginaFinal" => "12" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9804726" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides. J Exp Med 1945;82:445-65." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "MacLeod CM" 1 => "Hodges RG" 2 => "Heidelberg M" 3 => "Bernhard WG." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Exp Med" "fecha" => "1945" "volumen" => "82" "paginaInicial" => "445" "paginaFinal" => "65" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19871511" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pneumonia in old age: active immunization against pneumonia with pneumococcus polysaccharide-results of a six year study. Arch Intern Med 1947;79:518-31." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pneumonia in old age: active immunization against pneumonia with pneumococcus polysaccharide-results of a six year study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Kaufman P." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arch Intern Med" "fecha" => "1947" "volumen" => "79" "paginaInicial" => "518" "paginaFinal" => "31" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Immunisation with a polyvalent pneumococcal vaccine. Reduction of adult respiratory mortality in a New Guinea Highlands community. Lancet 1977;1:1338-41." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Immunisation with a polyvalent pneumococcal vaccine. Reduction of adult respiratory mortality in a New Guinea Highlands community." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Riley ID" 1 => "Tarr PI" 2 => "Andrews M" 3 => "Pfeiffer M" 4 => "Howard R" 5 => "Challands P" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1977" "volumen" => "1" "paginaInicial" => "1338" "paginaFinal" => "41" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2566875" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Protective efficacy of pneumococcal polysaccharide vaccines. JAMA 1977;238:2613-6." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Protective efficacy of pneumococcal polysaccharide vaccines." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Smit P" 1 => "Oberholzer D" 2 => "Hayden-Smith S" 3 => "Koornhof HJ" 4 => "Hilleman MR." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "1977" "volumen" => "238" "paginaInicial" => "2613" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21973" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Prevention of pneumococcal infection by immunization with capsular polysaccharides of Streptococcus pneumoniae: current status of polyvalent vaccines. J Infect Dis 1977; 136(Suppl 1):38-42." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Prevention of pneumococcal infection by immunization with capsular polysaccharides of Streptococcus pneumoniae: current status of polyvalent vaccines." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Austrian R." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "1977" "volumen" => "136" "paginaInicial" => "38" "paginaFinal" => "42" "itemHostRev" => array:3 [ "pii" => "S0266613813003069" "estado" => "S300" "issn" => "02666138" ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pneumococcal vaccine in the institutionalized elderly: design of a nonrandomized trial and preliminary results. Rev Infect Dis 1981;3(Suppl):71-81." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pneumococcal vaccine in the institutionalized elderly: design of a nonrandomized trial and preliminary results." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Bentley DW" 1 => "Ha K" 2 => "Mamot K" 3 => "Moon D" 4 => "Moore L" 5 => "Poletto P" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Infect Dis" "fecha" => "1981" "volumen" => "3" "paginaInicial" => "71" "paginaFinal" => "81" ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections. Ann Intern Med 1984; 101:325-30." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Shapiro ED" 1 => "Clemens JD." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "1984" "volumen" => "101" "paginaInicial" => "325" "paginaFinal" => "30" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6380367" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Essai clinique du vaccin antipneumococcique chez des personnes agees vivant en institution. Rev Epidemiol Sante Publique 1985;33:437-44." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Essai clinique du vaccin antipneumococcique chez des personnes agees vivant en institution." "idioma" => "fr" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Gaillat J" 1 => "Zmirou D" 2 => "Mallaret MR" 3 => "Rouhan D" 4 => "Bru JP" 5 => "Stahl JP" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Epidemiol Sante Publique" "fecha" => "1985" "volumen" => "33" "paginaInicial" => "437" "paginaFinal" => "44" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3914014" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pneumococcal vaccine efficacy in selected populations in the United States. Ann Intern Med 1986;104:1-6." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pneumococcal vaccine efficacy in selected populations in the United States." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Bolan G" 1 => "Broome CV" 2 => "Facklam RR" 3 => "Plikaytis BD" 4 => "Fraser DW" 5 => "Schlech WF." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "1986" "volumen" => "104" "paginaInicial" => "1" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3940476" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Placebo controlled pneumococcal immunization in patients with bronchogenic carcinoma. Eur J Cancer Clin Oncol 1986;22:807-13." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Placebo controlled pneumococcal immunization in patients with bronchogenic carcinoma." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Klastersky J" 1 => "Mommen P" 2 => "Cantraine F" 3 => "Safary A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Cancer Clin Oncol" "fecha" => "1986" "volumen" => "22" "paginaInicial" => "807" "paginaFinal" => "13" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3770039" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pneumococcal vaccine prevents death from acute lower-respiratory-tract infections in Papua New Guinean children. Lancet 1986;2:877-81." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pneumococcal vaccine prevents death from acute lower-respiratory-tract infections in Papua New Guinean children." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Riley ID" 1 => "Lehmann D" 2 => "Alpers MP" 3 => "Marshall TF" 4 => "Gratten H" 5 => "Smith D." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2215-0366(15)00422-8" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1986" "volumen" => "2" "paginaInicial" => "877" "paginaFinal" => "81" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26462224" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;315:1318-27." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Simberkoff MS" 1 => "Cross AP" 2 => "Al IM" 3 => "Baltch AL" 4 => "Geiseler PJ" 5 => "Nadler J" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM198611203152104" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1986" "volumen" => "315" "paginaInicial" => "1318" "paginaFinal" => "27" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3534568" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pneumococcal infection and immunologic response to pneumococcal vaccine in chronic obstructive pulmonary disease. A pilot study. Chest 1987;92:204-12." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pneumococcal infection and immunologic response to pneumococcal vaccine in chronic obstructive pulmonary disease. A pilot study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Davis AL" 1 => "Aranda CP" 2 => "Schiffman G" 3 => "Christianson LC." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Chest" "fecha" => "1987" "volumen" => "92" "paginaInicial" => "204" "paginaFinal" => "12" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3608590" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0266613807000150" "estado" => "S300" "issn" => "02666138" ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Inefficacy of pneumococcal vaccine in a high-risk population. Am J Med 1987; 83:425-30." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Inefficacy of pneumococcal vaccine in a high-risk population." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Forrester HL" 1 => "Jahnigen DW" 2 => "LaForce FM." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "1987" "volumen" => "83" "paginaInicial" => "425" "paginaFinal" => "30" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3661581" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease. CMAJ 1987;136:361-5." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Leech JA" 1 => "Gervais A" 2 => "Ruben FL." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "CMAJ" "fecha" => "1987" "volumen" => "136" "paginaInicial" => "361" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3545418" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med 1988;108:653-7." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The clinical effectiveness of pneumococcal vaccine in the elderly." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Sims RV" 1 => "Steinmann WC" 2 => "McConville JH" 3 => "King LR" 4 => "Zwick WC" 5 => "Schwartz JS." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "1988" "volumen" => "108" "paginaInicial" => "653" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3358567" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pneumococcal vaccine. Efficacy and associated cost savings. JAMA 1990;264:2910-5." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pneumococcal vaccine. Efficacy and associated cost savings." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Gable CB" 1 => "Holzer SS" 2 => "Engelhart L" 3 => "Friedman RB" 4 => "Smeltz F" 5 => "Schroeder D" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "1990" "volumen" => "264" "paginaInicial" => "2910" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2232086" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991;325: 1453-60." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The protective efficacy of polyvalent pneumococcal polysaccharide vaccine." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Shapiro ED" 1 => "Berg AT" 2 => "Austrian R" 3 => "Schroeder D" 4 => "Parcells V" 5 => "Margolis A" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199111213252101" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1991" "volumen" => "325" "paginaInicial" => "1453" "paginaFinal" => "60" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1944423" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pneumococcal polysaccharide vaccine efficacy. An evaluation of current recommendations. JAMA 1993;270:1826-31." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pneumococcal polysaccharide vaccine efficacy. An evaluation of current recommendations." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Butler JC" 1 => "Breiman RF" 2 => "Campbell JF" 3 => "Lipman HB" 4 => "Broome CV" 5 => "Facklam RR." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "1993" "volumen" => "270" "paginaInicial" => "1826" "paginaFinal" => "31" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8411526" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Preventing pneumococcal bacteremia in patients at risk. Results of a matched case-control study. Arch Intern Med 1995;155:2336-40." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Preventing pneumococcal bacteremia in patients at risk. Results of a matched case-control study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Farr BM" 1 => "Johnston BL" 2 => "Cobb DK" 3 => "Fisch MJ" 4 => "Germanson TP" 5 => "Adal KA" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "1995" "volumen" => "155" "paginaInicial" => "2336" "paginaFinal" => "40" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7487259" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial. Am J Med 1997;103:281-90." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Koivula I" 1 => "Sten M" 2 => "Leinonen M" 3 => "Makela PH." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "1997" "volumen" => "103" "paginaInicial" => "281" "paginaFinal" => "90" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9382120" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet 1998;351:399-403." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Ortqvist A" 1 => "Hedlund J" 2 => "Burman LA" 3 => "Elbel E" 4 => "Hofer M" 5 => "Leinonen M" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1998" "volumen" => "351" "paginaInicial" => "399" "paginaFinal" => "403" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9482293" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older. Vaccine 1999;17:2493-500." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Honkanen PO" 1 => "Keistinen T" 2 => "Miettinen L" 3 => "Herva E" 4 => "Sankilampi U" 5 => "Laara E" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Vaccine" "fecha" => "1999" "volumen" => "17" "paginaInicial" => "2493" "paginaFinal" => "500" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10418894" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease. Arch Intern Med 2000;159:2437-42." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Nichol KL" 1 => "Baken L" 2 => "Wuorenna J" 3 => "Nelson A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "2000" "volumen" => "159" "paginaInicial" => "2437" "paginaFinal" => "42" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10665892" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342:1878-86." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A comparison of observational studies and randomized, controlled trials." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Benson K" 1 => "Hartz AJ." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM200006223422506" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2000" "volumen" => "342" "paginaInicial" => "1878" "paginaFinal" => "86" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10861324" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887-92." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Randomized, controlled trials, observational studies, and the hierarchy of research designs." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Concato J" 1 => "Shah N" 2 => "Horwitz RI." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM200006223422507" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2000" "volumen" => "342" "paginaInicial" => "1887" "paginaFinal" => "92" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10861325" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Epidemiology of invasive Streptococcus pneumoniae infections in the United States, 1995-1998: opportunities for prevention in the conjugate vaccine era. JAMA 2001; 285:1729-35." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Epidemiology of invasive Streptococcus pneumoniae infections in the United States, 1995-1998: opportunities for prevention in the conjugate vaccine era." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Robinson KA" 1 => "Baughman W" 2 => "Rothrock G" 3 => "Barrett NL" 4 => "Pass M" 5 => "Lexau C" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2001" "volumen" => "285" "paginaInicial" => "1729" "paginaFinal" => "35" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11277827" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/02126567/0000003000000005/v0_201607121036/13037691/v0_201607121036/en/main.assets" "Apartado" => array:4 [ "identificador" => "14695" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Originales" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/02126567/0000003000000005/v0_201607121036/13037691/v0_201607121036/en/27v30n05a13037691pdf001.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037691?idApp=UINPBA00004N"]

Statistics

Pneomococcal vaccine effectiveness in the elderly. Systematic review and meta-analysis

Efectividad de la vacuna frente al neomococo en el anciano. Revisión sistemática y metaanalisis

J. Puig-Barberàa, A. Belenguer Vareab, M. Goterris Pintoc, MJ. Brines Benlliurec

a Health Promotion, Castellón Public Health Center, Castellón, Spain. Working Group on Vaccines, Valencian Society of Family and Community Medicine (SVMFYC). Spain.

b Geriatrics Unit, Internal Medicine Service, Hospital de la Rivera, Alzira, Valencia, Spain.

c Burriana Health Center, Burriana, Castellón, Spain.

Read

6552

Times
was read the article

1104

Total PDF

5448

Total HTML

Share statistics

 array:21 [
  "pii" => "13037691"
  "issn" => "02126567"
  "estado" => "S300"
  "fechaPublicacion" => "2002-09-30"
  "documento" => "article"
  "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
  "subdocumento" => "fla"
  "cita" => "Aten Primaria. 2002;30:269-82"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 3894
    "formatos" => array:3 [
      "EPUB" => 61
      "HTML" => 3229
      "PDF" => 604
    ]
  ]
  "Traduccion" => array:1 [
    "es" => array:16 [
      "pii" => "13037447"
      "issn" => "02126567"
      "estado" => "S300"
      "fechaPublicacion" => "2002-09-30"
      "documento" => "article"
      "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
      "subdocumento" => "fla"
      "cita" => "Aten Primaria. 2002;30:269-82"
      "abierto" => array:3 [
        "ES" => true
        "ES2" => true
        "LATM" => true
      ]
      "gratuito" => true
      "lecturas" => array:2 [
        "total" => 8651
        "formatos" => array:3 [
          "EPUB" => 55
          "HTML" => 6419
          "PDF" => 2177
        ]
      ]
      "es" => array:11 [
        "idiomaDefecto" => true
        "titulo" => "Efectividad de la vacuna frente al neumococo en el anciano&#46; Revisi&#243;n sistem&#225;tica y metaan&#225;lisis"
        "tienePdf" => "es"
        "tieneTextoCompleto" => "es"
        "tieneResumen" => array:2 [
          0 => "es"
          1 => "en"
        ]
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "269"
            "paginaFinal" => "282"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Pneomococcal vaccine effectiveness in the elderly&#46; Systematic review and meta-analysis"
          ]
        ]
        "contieneResumen" => array:2 [
          "es" => true
          "en" => true
        ]
        "contieneTextoCompleto" => array:1 [
          "es" => true
        ]
        "contienePdf" => array:1 [
          "es" => true
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "J Puig-Barber&#224;, A Belenguer Varea, M Goterris Pinto, MJ Brines Benlliure"
            "autores" => array:4 [
              0 => array:2 [
                "Iniciales" => "J"
                "apellidos" => "Puig-Barber&#224;"
              ]
              1 => array:2 [
                "Iniciales" => "A"
                "apellidos" => "Belenguer Varea"
              ]
              2 => array:2 [
                "Iniciales" => "M"
                "apellidos" => "Goterris Pinto"
              ]
              3 => array:2 [
                "Iniciales" => "MJ"
                "apellidos" => "Brines Benlliure"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "es"
      "Traduccion" => array:1 [
        "en" => array:8 [
          "pii" => "13037691"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => true
            "ES2" => true
            "LATM" => true
          ]
          "gratuito" => true
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "en"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037691?idApp=UINPBA00004N"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037447?idApp=UINPBA00004N"
      "url" => "/02126567/0000003000000005/v0_201607121036/13037447/v0_201607121036/es/main.assets"
    ]
  ]
  "itemSiguiente" => array:16 [
    "pii" => "13037692"
    "issn" => "02126567"
    "estado" => "S300"
    "fechaPublicacion" => "2002-09-30"
    "documento" => "article"
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Aten Primaria. 2002;30:283"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 1816
      "formatos" => array:3 [
        "EPUB" => 62
        "HTML" => 1445
        "PDF" => 309
      ]
    ]
    "en" => array:9 [
      "idiomaDefecto" => true
      "titulo" => "Commentary&#58; Pneumococcal disease&#58; is prevention possible&#63;"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:1 [
          "paginaInicial" => "283"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Comentario&#58; Enfermedad neumoc&#243;cica&#58; &#191;es posible la prevenci&#243;n&#63;"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "MJ &#193;lvarez Pasqu&#237;n, JJ G&#243;mez Marco"
          "autores" => array:2 [
            0 => array:2 [
              "Iniciales" => "MJ"
              "apellidos" => "&#193;lvarez Pasqu&#237;n"
            ]
            1 => array:2 [
              "Iniciales" => "JJ"
              "apellidos" => "G&#243;mez Marco"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:8 [
        "pii" => "13037449"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037449?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037692?idApp=UINPBA00004N"
    "url" => "/02126567/0000003000000005/v0_201607121036/13037692/v0_201607121036/en/main.assets"
  ]
  "itemAnterior" => array:16 [
    "pii" => "13037447"
    "issn" => "02126567"
    "estado" => "S300"
    "fechaPublicacion" => "2002-09-30"
    "documento" => "article"
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Aten Primaria. 2002;30:269-82"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 8651
      "formatos" => array:3 [
        "EPUB" => 55
        "HTML" => 6419
        "PDF" => 2177
      ]
    ]
    "es" => array:11 [
      "idiomaDefecto" => true
      "titulo" => "Efectividad de la vacuna frente al neumococo en el anciano&#46; Revisi&#243;n sistem&#225;tica y metaan&#225;lisis"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "269"
          "paginaFinal" => "282"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Pneomococcal vaccine effectiveness in the elderly&#46; Systematic review and meta-analysis"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "J Puig-Barber&#224;, A Belenguer Varea, M Goterris Pinto, MJ Brines Benlliure"
          "autores" => array:4 [
            0 => array:2 [
              "Iniciales" => "J"
              "apellidos" => "Puig-Barber&#224;"
            ]
            1 => array:2 [
              "Iniciales" => "A"
              "apellidos" => "Belenguer Varea"
            ]
            2 => array:2 [
              "Iniciales" => "M"
              "apellidos" => "Goterris Pinto"
            ]
            3 => array:2 [
              "Iniciales" => "MJ"
              "apellidos" => "Brines Benlliure"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "Traduccion" => array:1 [
      "en" => array:8 [
        "pii" => "13037691"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "en"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037691?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037447?idApp=UINPBA00004N"
    "url" => "/02126567/0000003000000005/v0_201607121036/13037447/v0_201607121036/es/main.assets"
  ]
  "asociados" => array:1 [
    0 => array:16 [
      "pii" => "13037692"
      "issn" => "02126567"
      "estado" => "S300"
      "fechaPublicacion" => "2002-09-30"
      "documento" => "article"
      "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
      "subdocumento" => "fla"
      "cita" => "Aten Primaria. 2002;30:283"
      "abierto" => array:3 [
        "ES" => true
        "ES2" => true
        "LATM" => true
      ]
      "gratuito" => true
      "lecturas" => array:2 [
        "total" => 1816
        "formatos" => array:3 [
          "EPUB" => 62
          "HTML" => 1445
          "PDF" => 309
        ]
      ]
      "en" => array:9 [
        "idiomaDefecto" => true
        "titulo" => "Commentary&#58; Pneumococcal disease&#58; is prevention possible&#63;"
        "tienePdf" => "en"
        "tieneTextoCompleto" => "en"
        "paginas" => array:1 [
          0 => array:1 [
            "paginaInicial" => "283"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Comentario&#58; Enfermedad neumoc&#243;cica&#58; &#191;es posible la prevenci&#243;n&#63;"
          ]
        ]
        "contieneTextoCompleto" => array:1 [
          "en" => true
        ]
        "contienePdf" => array:1 [
          "en" => true
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "MJ &#193;lvarez Pasqu&#237;n, JJ G&#243;mez Marco"
            "autores" => array:2 [
              0 => array:2 [
                "Iniciales" => "MJ"
                "apellidos" => "&#193;lvarez Pasqu&#237;n"
              ]
              1 => array:2 [
                "Iniciales" => "JJ"
                "apellidos" => "G&#243;mez Marco"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "en"
      "Traduccion" => array:1 [
        "es" => array:8 [
          "pii" => "13037449"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => true
            "ES2" => true
            "LATM" => true
          ]
          "gratuito" => true
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "es"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037449?idApp=UINPBA00004N"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037692?idApp=UINPBA00004N"
      "url" => "/02126567/0000003000000005/v0_201607121036/13037692/v0_201607121036/en/main.assets"
    ]
  ]
  "en" => array:14 [
    "idiomaDefecto" => true
    "titulo" => "Pneomococcal vaccine effectiveness in the elderly&#46; Systematic review and meta-analysis"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "269"
        "paginaFinal" => "282"
      ]
    ]
    "autores" => array:1 [
      0 => array:3 [
        "autoresLista" => "J Puig-Barber&#224;, A Belenguer Varea, M Goterris Pinto, MJ Brines Benlliure"
        "autores" => array:4 [
          0 => array:3 [
            "Iniciales" => "J"
            "apellidos" => "Puig-Barber&#224;"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "affa"
              ]
            ]
          ]
          1 => array:3 [
            "Iniciales" => "A"
            "apellidos" => "Belenguer Varea"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "affb"
              ]
            ]
          ]
          2 => array:3 [
            "Iniciales" => "M"
            "apellidos" => "Goterris Pinto"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "affc"
              ]
            ]
          ]
          3 => array:3 [
            "Iniciales" => "MJ"
            "apellidos" => "Brines Benlliure"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "affc"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:3 [
          0 => array:3 [
            "entidad" => "Health Promotion, Castellón Public Health Center, Castellón, Spain. Working Group on Vaccines, Valencian Society of Family and Community Medicine (SVMFYC). Spain."
            "etiqueta" => "<span class="elsevierStyleSup">a</span>"
            "identificador" => "affa"
          ]
          1 => array:3 [
            "entidad" => "Geriatrics Unit, Internal Medicine Service, Hospital de la Rivera, Alzira, Valencia, Spain."
            "etiqueta" => "<span class="elsevierStyleSup">b</span>"
            "identificador" => "affb"
          ]
          2 => array:3 [
            "entidad" => "Burriana Health Center, Burriana, Castellón, Spain."
            "etiqueta" => "<span class="elsevierStyleSup">c</span>"
            "identificador" => "affc"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "en" => array:1 [
        "titulo" => "Efectividad de la vacuna frente al neomococo en el anciano&#46; Revisi&#243;n sistem&#225;tica y metaanalisis"
      ]
    ]
    "textoCompleto" => "<p class="elsevierStylePara">Introduction</p><hr></hr><p class="elsevierStylePara">The indications for pneumococcal vaccination in persons aged 65 years or more are controversial because of discordant results between different studies&#44;<span class="elsevierStyleSup">1-4</span> and important differences have been noted in international recommendations for vaccination in this age group&#46;<span class="elsevierStyleSup">2&#44;5&#44;6</span> The controversy first appeared at the beginning of the 1980s in the light of difficulties large clinical trials had in demonstrating the effectiveness of vaccination in older persons&#44;<span class="elsevierStyleSup">7</span> and it was argued that the large numbers of participants required to guarantee sufficient statistical power to prove the protective efficacy of vaccination made such clinical trials impracticable&#46;<span class="elsevierStyleSup">8</span> At the end of the 1980s&#44; recommendations for vaccination in persons older than 65 years were based on the results of observational studies&#46; It is therefore high time for a systematic&#44; thorough review of the literature&#44; which now includes clinical trials and observational studies&#46; Methodological quality criteria can now be used to guarantee an unbiased estimate of the effectiveness of pneumococcal vaccination in older persons&#46;</p><hr></hr><p class="elsevierStylePara">Methodology</p><hr></hr><p class="elsevierStylePara"><img src="27v30n05-13037691tab01.gif"></img></p><p class="elsevierStylePara">To estimate the effectiveness of 23-valent pneumococcal capsular polysaccharide vaccination in preventing the disease caused by pneumococcal organisms in persons older than 65 years&#44; we systematically reviewed the literature&#44; with attention to both clinical trials and observational studies&#46; Bibliographic databases were searched for articles published in Spanish&#44; English or French between the years 1964 and 2000 in MEDLINE&#44; and between 1988 and 2000 in EMBASE&#46; The CD-ROM edition of the Cochrane Library database<span class="elsevierStyleSup">9</span> was searched up to and including the first disk issued in 2001&#46; Previously unidentified items were searched for in the reference lists of retrieved articles and in those of four separate reviews &#40;three of which were systematic&#41; of the effectiveness of polysaccharide vaccines&#46;<span class="elsevierStyleSup">1-4</span> Researchers were contacted to request unpublished information and other unidentified items&#46;</p><p class="elsevierStylePara">Two search strategies were used&#58; the sensitive strategy was based on the terms <span class="elsevierStyleItalic">pneumoc<span class="elsevierStyleSup">&#42;</span> AND vaccin<span class="elsevierStyleSup">&#42;</span> AND elderly</span>&#44; and the specific strategy used the terms <span class="elsevierStyleItalic"> pneumoc<span class="elsevierStyleSup">&#42;</span> AND vaccin<span class="elsevierStyleSup">&#42;</span> AND elderly AND &#40;effectiv<span class="elsevierStyleSup">&#42;</span> OR effica<span class="elsevierStyleSup">&#42;</span>&#41;</span>&#46; We retrieved clinical trials&#44; cohort studies and case-control studies that reported results for the effect of vaccination on the risk of pneumococcal disease&#44; defined as pneumococcal pneumonia or invasive disease caused by pneumococci of the serotypes included in the vaccine and identified by culture&#44; in populations of adults aged 65 years or older&#46; Invasive disease was defined by the isolation of pneumococcal organisms from a normally sterile anatomical site&#46; <span class="elsevierStyleSup">12</span>&#46;</p><p class="elsevierStylePara">Inclusion&#44; exclusion and evaluation criteria for studies</p><p class="elsevierStylePara">Studies were evaluated independently by four researchers on the basis of predefined criteria for validity&#46;<span class="elsevierStyleSup">10-13</span> Differences were resolved by consensus between the researchers&#46; The inclusion criteria used to select studies were&#58; <span class="elsevierStyleItalic">a&#41;</span> information included on the administration of the vaccine in adults aged 65 years or more&#59; <span class="elsevierStyleItalic">b&#41;</span> risk measured for pneumonia or invasive disease caused by pneumococci belonging to the serotypes included in the vaccine&#59; <span class="elsevierStyleItalic">c&#41;</span> information included on the comparability of cases and controls or exposed and unexposed persons&#44; ie&#44; information that both of the groups being compared belonged to the same study base&#59;<span class="elsevierStyleSup">14</span><span class="elsevierStyleItalic">d&#41;</span> random allocation according to an adequately concealed double-blind procedure in clinical trials&#59;<span class="elsevierStyleSup">15</span><span class="elsevierStyleItalic">e&#41;</span> response rates higher than 80&#37; for observational studies&#44; or drop-out rates lower than 10&#37; for clinical trials&#59;<span class="elsevierStyleSup">16</span><span class="elsevierStyleItalic">f&#41;</span> absence of classification bias or serious violations of blinding&#59;<span class="elsevierStyleSup">15</span><span class="elsevierStyleItalic">g&#41;</span> suitable control of confounding variables&#44; and <span class="elsevierStyleItalic">h&#41;</span> sufficient information to be able to repeat the analysis&#46;<span class="elsevierStyleSup">17</span> Noncompliance with either of the first two criteria &#40;<span class="elsevierStyleItalic">a</span> or <span class="elsevierStyleItalic">b</span>&#41; led to exclusion of the study&#46; The other criteria were used as parameters to evaluate the quality of the studies&#44; which were classified according to the following matrix&#58;<span class="elsevierStyleSup">12</span></p><p class="elsevierStylePara"><img src="27v30n05-13037691tab02.gif"></img></p><p class="elsevierStylePara">We excluded from the quantitative analysis all studies classified as C&#44; and included all those classified as A or B&#46;</p><p class="elsevierStylePara">Analysis</p><p class="elsevierStylePara">A descriptive analysis was prepared based on the year of publication&#44; age groups included&#44; type of population&#44; study design&#44; number of serotypes included in the vaccine&#44; type of results studied and number of participants&#59; relative risks &#40;RR&#41; were estimated and their confidence intervals &#40;CI&#41; calculated&#46; Because of the low frequency of the events of interest&#44; the odds ratio was considered an unbiased estimator of the RR&#46; For each study we recorded factors that compromised the validity of the estimates and the likelihood that the results were biased&#46;</p><p class="elsevierStylePara">Before estimating the protective effect of vaccination&#44; we evaluated the homogeneity of the studies with graphs that illustrated point estimates of RR for pneumococcal disease and the CI&#44; and their overlap or divergence&#46; The hypothesis of homogeneity was tested by estimating the chi-squared value&#59;<span class="elsevierStyleSup">18</span> significant heterogeneity was considered to exist when <span class="elsevierStyleItalic"> P</span>&#60;&#46;10&#46; The possibility of publication bias was explored with the test of Egger et al&#46;<span class="elsevierStyleSup">19</span> The degree to which heterogeneity of the estimates was influenced by study characteristics such as design&#44; number of serotypes in the vaccine&#44; year and biases was studied by regression &#40;metaregression analysis&#41; of these characteristics on the logarithm of RR&#46;<span class="elsevierStyleSup">20</span> Only when the inclusion and validity criteria were satisfied and homogeneity could not be ruled out did we estimate the aggregate RR and its CI with the random effects method of DerSimonian and Laird<span class="elsevierStyleSup">18</span> for a 95&#37; confidence interval&#46; When the confidence interval of the estimated RR included 1&#44; we interpreted this to mean that vaccination did not confer significant protection against pneumococcal disease&#46; The aggregate effectiveness of vaccination was calculated as &#40;1&#173;RR&#41;&#42;100&#46;<span class="elsevierStyleSup">21</span></p><p class="elsevierStylePara">The number needed to treat &#40;NNT&#41; to avoid the outcomes of interest was also calculated&#46;<span class="elsevierStyleSup">22&#44;23</span> All calculations were done with MS-Excel&#44; MS-Access&#44; Epi Info v&#46; 6&#46;04b and STATA v&#46; 5 software&#46;</p><hr></hr><p class="elsevierStylePara">Results </p><hr></hr><p class="elsevierStylePara">Twenty-five items were identified that compared the effectiveness of pneumococcal vaccination in preventing pneumococcal disease versus a control group&#46;<span class="elsevierStyleSup">7&#44;24-47</span> Four articles were excluded because they dealt with young adults or Children&#44;<span class="elsevierStyleSup">24&#44;27&#44;28&#44;34</span> and a fifth item was excluded because it included individuals aged 10 years or more&#44; did not supply information on age groups&#44; and was done in a setting that made it difficult to extrapolate the results to western populations&#46;<span class="elsevierStyleSup">26</span> Of the remaining 20 articles &#40;Table 1&#41;&#44; 11 were clinical trials<span class="elsevierStyleSup">7&#44;25&#44;29&#44;31&#44;33&#44;35&#44;36&#44;38&#44;44-46</span> and 9 were observational studies&#46;<span class="elsevierStyleSup">30&#44;32&#44;37&#44;39-43&#44;47</span></p><p class="elsevierStylePara"><img src="27v30n05-13037691tab03.gif"></img></p><p class="elsevierStylePara"><img src="27v30n05-13037691tab04.gif"></img></p><p class="elsevierStylePara">Of the 11 clinical trials retrieved&#44; eight analyzed the efficacy of the vaccine in preventing pneumococcal disease caused by serotypes included in the vaccine&#46;<span class="elsevierStyleSup">7&#44;25&#44;29&#44;31&#44;33&#44;35&#44;45&#44;46</span> Six studies &#40;Table 2&#41; had one or both of the following problems&#58; appropriate random allocation of the participants to the experimental or control group was not used&#44; or the allocation procedure was not adequately concealed from the researchers and participants in the treatment group&#46;<span class="elsevierStyleSup">25&#44;29&#44;31&#44;33&#44;44&#44;46</span> For the five remaining studies we estimated a low or moderate likelihood of bias&#44; as participants were assigned randomly to one group or the other&#44; and because researchers and participants were appropriately blinded to the procedure&#46;<span class="elsevierStyleSup">7&#44;35&#44;36&#44;38&#44;45</span></p><p class="elsevierStylePara"><img src="27v30n05-13037691tab05.gif"></img></p><p class="elsevierStylePara">Of the nine observational studies we retrieved&#44; four analyzed the effectiveness of the vaccine in preventing pneumococcal disease caused by serotypes included in the vaccine&#44;<span class="elsevierStyleSup">32&#44;37&#44;41&#44;42</span> and six were judged highly likely to be biased &#40;Table 3&#41;&#46; The patients described in the study by Bolan et al&#46;<span class="elsevierStyleSup">32</span> were included in the study by Butler et al&#46;&#59;<span class="elsevierStyleSup">42</span> the former did not provide any indication of the thoroughness of the information regarding exposure&#44; whereas the second lacked information about exposure for 39&#37; of the participants eligible for inclusion&#46; We therefore considered the validity of these estimates to be insufficient&#46; In the study by Sims et al&#46;&#44;<span class="elsevierStyleSup">39</span> 107 participants &#40;46&#37;&#41; of a total of 229 were excluded because information about exposure was missing&#46; The two studies by Shapiro et al&#46; published in 1984<span class="elsevierStyleSup">30</span> and 1991<span class="elsevierStyleSup">41</span> had characteristics that met the criteria for estimates of moderate validity&#44; and also presented estimates that changed direction when the analysis was repeated after ignoring the case-control matching<span class="elsevierStyleSup">30</span> or after information for 122 participants vaccinated with the 23-valent capsule polysaccharide vaccine was excluded&#46;<span class="elsevierStyleSup">41</span> The study by Gable et al&#46;<span class="elsevierStyleSup">40</span> was based on administrative data&#44; and the analysis was inadequate&#46; Lastly&#44; in the study by Nichols et al&#46;<span class="elsevierStyleSup">47</span> exposed &#40;vaccinated&#41; and unexposed &#40;unvaccinated&#41; individuals could not be considered members of the same population at risk&#46;</p><p class="elsevierStylePara"><img src="27v30n05-13037691tab06.gif"></img></p><p class="elsevierStylePara">Effect of vaccination on pneumococcal pneumonia caused by serotypes included in the vaccine</p><p class="elsevierStylePara">Eight of the clinical trials retrieved &#40;Table 1&#44; Figure 1a&#41; estimated the RR of pneumococcal pneumonia in vaccinated versus unvaccinated persons&#46;<span class="elsevierStyleSup">7&#44;25&#44;29&#44;31&#44;35&#44;36&#44;45&#44;46</span> Three studies<span class="elsevierStyleSup">36&#44;45&#44;46</span> did not estimate the number of cases of pneumococcal pneumonia caused by serotypes included in the vaccine &#40;Table 2&#41;&#46; Only the study by Kaufman et al&#46;&#44;<span class="elsevierStyleSup">25</span> who investigated a vaccine composed of three capsular serotypes &#40;Table 1&#41;&#44; reported a favorable estimate of the vaccine&#180;s protective efficacy&#46; As shown in Figures 1a and 1b&#44; this study cannot be considered similar to the others carried out between 1980 and 1998&#46; None of the other clinical trials found a clinically significant protective effect &#40;RR&#41; for vaccination &#40;Figure 1b&#41;&#46; Figure 1c shows the estimates from those three trials &#40;from among the original eight studies&#41; that fulfilled the criteria for validity of the estimates &#40;Table 2&#41;&#46; The trial published by Austrian et al&#46;<span class="elsevierStyleSup">7</span> was excluded because samples for the identification of the serotype that caused pneumonia were obtained from fewer than 75&#37; of the patients&#44; although&#173;as shown in Figure 1 and Table 1&#173;none of their estimates showed vaccination to be protective&#46; Lastly&#44; only the clinical trial reported by Simberkoff et al&#46;<span class="elsevierStyleSup">35</span> in 1986 fulfilled the inclusion criteria for validity of the estimates and for our definition of a case&#58; these authors provided estimates of the risk of pneumococcal pneumonia according to each serotype included in the vaccine&#46;</p><p class="elsevierStylePara"><img src="27v30n05-13037691tab07.gif"></img></p><p class="elsevierStylePara">Figure 1&#46; Relative risks of pneumococcal pneumonia&#46; Part a shows all studies that measured the effectiveness of vaccination in preventing this disease&#59; the test for homogeneity yielded a chi-squared value of 191&#46;63 with 7 degrees of freedom and <span class="elsevierStyleItalic">P</span>&#60;&#46;001&#46; Part b shows that after the study by Kaufman et al&#46;<span class="elsevierStyleSup">25</span> was excluded&#44; the test for homogeneity yielded a chi-squared value of 2&#46;69 with 7 degrees of freedom and <span class="elsevierStyleItalic">P</span>&#60;&#46;85&#46; Part c shows the three studies that calculated the RR for pneumococcal pneumonia in vaccinated versus unvaccinated persons and that fulfilled our methodological quality criteria&#46; However&#44; two studies &#40;Davis et al&#46;<span class="elsevierStyleSup">36</span> and Ortqvist et al&#46;<span class="elsevierStyleSup">45</span>&#41; failed to investigate the serotypes that caused the disease&#46; The areas of the boxes reflect the precision of the estimates obtained in different studies&#46;</p><p class="elsevierStylePara">The best available estimate placed the RR for pneumococcal pneumonia in vaccinated individuals compared to unvaccinated individuals at 0&#46;86&#44; with a 95&#37; CI of 0&#46;24 to 2&#46;99&#46; Effectiveness in preventing pneumococcal pneumonia caused by the serotypes in the vaccine was 14&#37;&#44; with a 95&#37; CI of &#173;199&#37; to 76&#37;&#46; The number of individual needed to vaccinate &#40;NNT&#41; to prevent one case was 1197&#46; The CI indicated the possibility that one case of pneumococcal pneumonia could be caused for every 85 or more persons vaccinated&#44; and that one case could be prevented for every 242 or more persons vaccinated&#59; this CI also included zero Table 4&#41;&#46;</p><p class="elsevierStylePara"><img src="27v30n05-13037691tab08.gif"></img></p><p class="elsevierStylePara">Effect of vaccination on invasive disease caused by serotypes included in the vaccine</p><p class="elsevierStylePara">Ten studied provided estimates of the effectiveness of vaccination against invasive disease caused by serotypes included in the vaccine &#40;Figure 2a&#41;&#46; Only three studies &#40;Kaufman et al&#46;&#44;<span class="elsevierStyleSup">25</span> Bolan et al&#46;<span class="elsevierStyleSup">32</span> and Butler et al&#46;<span class="elsevierStyleSup">42</span>&#41; concluded that vaccination was significantly superior to the placebo &#40;Figure 2a&#41;&#46; The study by Kaufman et al&#46;<span class="elsevierStyleSup">25</span> had important limitations regarding random allocation of the participants and blinding of the investigators&#59; the studies by Bolan et al&#46;<span class="elsevierStyleSup">32</span> and Butler et al&#46;<span class="elsevierStyleSup">42</span> reported results for the same series of patients and did not provide information on exposure for a large percentage of participants&#46; The studies by Bentley et al&#46;&#44;<span class="elsevierStyleSup">29</span> Klastersky et al&#46;<span class="elsevierStyleSup">33</span> and Honkanen et al&#46;<span class="elsevierStyleSup">46</span> did not satisfy the criteria because of problems with random allocation of the participants to different interventions&#44; or problems with blinding the investigators or the participants &#40;Table 2&#41;&#46;</p><p class="elsevierStylePara"><img src="27v30n05-13037691tab09.gif"></img></p><p class="elsevierStylePara">Figure 2&#46; a&#41; Estimates of relative risk &#40;RR&#41; of invasive disease caused by the pneumococcal serotypes included in the vaccine and the 95&#37; confidence intervals &#40;95&#37; CI&#41;&#46; For all studies retrieved&#44; the test for homogeneity yielded a chi-squared value of 16&#46;12 with 9 degrees of freedom and <span class="elsevierStyleItalic">P</span>&#61;&#46;06&#46; The x axis scale has been truncated on both ends to improve legibility&#46; b&#41; Estimates of RR and 95&#37; CI for the studies that fulfilled our inclusion criteria&#46; Global RR was 0&#46;68&#44; 95&#37; CI was 0&#46;39 to 1&#46;18&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;17&#46; The test for homogeneity yielded a chi-squared value of 2&#46;09 with 3 degrees of freedom and <span class="elsevierStyleItalic">P</span>&#61;&#46;55&#46; The areas of the boxes reflect the precision of the estimates obtained in different studies&#46;</p><p class="elsevierStylePara">Of the 10 studies we examined&#44; the clinical trials by Simberkoff et al&#46;<span class="elsevierStyleSup">35</span> and Ortqvist et al&#46;&#44;<span class="elsevierStyleSup">45</span> and the observational studies by Forrester et al&#46;<span class="elsevierStyleSup">37</span> and Shapiro et al&#46;<span class="elsevierStyleSup">41</span> fulfilled our methodological quality criteria well enough so that we could trust the validity of their results &#40;Tables 2 and 3&#41;&#46; The aggregate RR for invasive disease was 0&#46;68&#44; with a 95&#37; CI of 0&#46;39 to 1&#46;18 and a <span class="elsevierStyleItalic">P</span>&#61;&#46;17 &#40;Figure 2b&#41;&#46; The chi-squared test used to check the hypothesis of homogeneity of the different studies yielded a value of 2&#46;09 with 3 degrees of freedom and a <span class="elsevierStyleItalic">P</span>&#61;&#46;55&#46; The test of Egger et al&#46; used to determine the possibility of publication bias yielded a nonsignificant value of <span class="elsevierStyleItalic">P</span>&#61;&#46;79&#46; Effectiveness of vaccination was 32&#37;&#44; with a 95&#37; CI of &#173;18&#37; to 51&#37;&#44; a result that implied that vaccination had no significant effect&#46;</p><p class="elsevierStylePara">The estimated number of individuals needed to vaccinate &#40;NNT&#41; to prevent one case of invasive disease was 785&#44; with a CI that showed that one case of invasive disease might be caused for every 1399 or more persons vaccinated&#44; and that one case might be prevented for every 412 persons or more vaccinated&#46; The CI again included zero &#40;Table 4&#41;&#46;</p><p class="elsevierStylePara">Sensitivity analysis</p><p class="elsevierStylePara">Figure 1a illustrates the effectiveness of vaccination in preventing pneumococcal pneumonia according to different studies&#46; The results of the study by Kaufman et al&#46;<span class="elsevierStyleSup">25</span> explained the heterogeneity in the estimates of risk for pneumococcal pneumonia&#59; this was further confirmed by metaregression analysis&#44; which showed no significant alterations in the results according to the number of serotypes included in the vaccine&#44; the year the study was done&#44; or publication bias after the Kaufman et al&#46; study was excluded&#46;</p><p class="elsevierStylePara">Figure 2a shows that the results of studies that investigated the effectiveness of the vaccine in preventing invasive disease were markedly heterogeneous&#46; Metaregression on the logarithm of RR and analysis of the influence of the year of the study&#44; the study design&#44; the serotypes included in the vaccine or publication bias showed that this last factor was the one that best explained &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;009&#41; the variability in our results &#40;Figure 3&#41;&#46; In fact&#44; the point estimate of effectiveness of the vaccination was 2&#46;6-fold greater in studies for which we considered validity of the estimates to be compromised than in studies we considered free from bias &#40;classified as A or B&#41;&#46; The RR increased from 0&#46;26 to 0&#46;68&#44; and the CI for the latter value indicated that the effect of vaccination was null&#46;</p><p class="elsevierStylePara"><img src="27v30n05-13037691tab10.gif"></img></p><p class="elsevierStylePara">Figura 3&#46; Results of metaregression analysis of the effect of publication bias on estimates of the effectiveness of vaccination in preventing invasive disease&#46; Estimates for studies classified as A or B were significantly different &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;004&#41; from estimates obtained for studies classified as C&#46; Interpretation of values along the x axis&#58; A&#44; A Low likelihood of bias&#59; B&#44; moderate likelihood of bias&#59; C&#44; high likelihood of bias &#40;see Methods section&#41;&#46;</p><hr></hr><p class="elsevierStylePara">Discussion </p><hr></hr><p class="elsevierStylePara"><img src="27v30n05-13037691tab11.gif"></img></p><p class="elsevierStylePara">Twenty-five years after vaccination with capsular polysaccharide vaccines for pneumococci was first authorized&#44; uncertainty remains as to their effectiveness&#44; and some authors have warned that recommendations in favor of systematic vaccination for all persons aged 65 years or more need to be reviewed in the light of current knowledge&#46;<span class="elsevierStyleSup">4</span> This situation has been fomented by proponents of vaccination who claimed that clinical trials would be impracticable and that observational studies were sufficient&#46;<span class="elsevierStyleSup">8</span> The present sytematic review of the literature and meta-analysis included both observational studies and clinical trials&#44; and obtained estimates of the effectiveness of vaccination in which the lower limit of the CI was a negative value&#46; In other words&#44; we found no proof of the effectiveness of pneumococcal vaccine in reducing or preventing pneumococcal disease in older persons&#46; These results are in agreement with the findings of Fine et al&#46;<span class="elsevierStyleSup">1</span> and Moore et al&#46;&#44;<span class="elsevierStyleSup">4</span> who included in their reviews only clinical assays&#46;</p><p class="elsevierStylePara">Several factors may compromise the results of a systematic review of the literature&#46;<span class="elsevierStyleSup">19</span> One possible source of bias is that studies eligible for inclusion may be overlooked because the predominance of publications in English makes studies in other languages less likely to be cited and retrieved&#46; Another possible bias arises from the fact that the databases we used for our literature searches are selective in the references they include&#46; Moreover&#44; unpublished studies&#173;most of which report negative findings&#173;are not retrieved&#46; In the present study we did not limit our searches to studies in English&#46; We searched MEDLINE&#44; EMBASE and the Cochrane Library&#44; and made appropriate efforts to retrieve unpublished studies such as those by Austrian et al&#46;&#44;<span class="elsevierStyleSup">7</span> a clinical trial with adequately concealed random allocation&#44; double-blinding and a large number of participants &#40;13 600&#41;&#46; We contacted other researchers to obtain information on additional publications and scrutinized the reference lists of the items retrieved from database searches&#46; In fact&#44; the results of the test of Eggar et al&#46;&#44; which we applied to studies that investigated invasive disease&#44; supported our assumption that no bias was introduced by the noninclusion of studies that might have been overlooked&#46;<span class="elsevierStyleSup">19</span></p><p class="elsevierStylePara">Another source of error is bias in the choice and application of inclusion and exclusion criteria&#44; data extraction and quality control criteria&#46; To avoid these pitfalls the aims and inclusion criteria were defined before the study was begun&#46;<span class="elsevierStyleSup">12</span> Moreover&#44; we included both clinical trials and observational studies&#46; All items were reviewed and assessed independently by the authors&#44; who all used the same methods of analysis&#46;</p><p class="elsevierStylePara">With regard to the studies we included&#44; possible sources of heterogeneity were reduced by adapting our selection process to the question that formed the basis of the present analysis&#46; The use of age as an inclusion criterion led us to exclude studies of children or young adults&#44; in whom the response to vaccination differs from that in older persons&#59;<span class="elsevierStyleSup">1</span> in addition&#44; we opted to include only those studies with unambiguous clinical outcomes that evaluated the protection conferred against pneumococcal pneumonia or invasive disease caused by <span class="elsevierStyleItalic">S&#46; pneumonia</span> serotypes included in the vaccine&#46;</p><p class="elsevierStylePara">A further potential source of heterogeneity between studies included in our analysis is the aggregation of results of clinical assays and observational studies&#46; However&#44; for studies designed and executed with adequate guarantees of methodological rigor&#44; the results of clinical trials and observational studies concur&#46;<span class="elsevierStyleSup">48&#44;49</span> Heterogeneity of the findings from included and excluded studies &#40;Figure 2a&#41; was explained mainly by the presence or absence of factors that compromised the validity of the estimates &#40;Figure 3&#41;&#44; as opposed to factors such as the type of study design&#44; year of publication or number of serotypes in the vaccine&#44; which had no significant influence on the results&#46;</p><p class="elsevierStylePara">In comparison to fixed effect models&#44; our random effects statistical model can be considered an appropriate method for aggregating data from different studies&#46; The former approach assumes that differences in the estimates are caused only by sampling error&#44; whereas the random effects model also takes into account the fact that because the characteristics of the participants were not homogeneous across the studies we included&#44; the magnitude of the effects of vaccination differed between studies&#46; This was in fact the case in the present review&#58; the studies we retrieved involved populations that differed in their risk profiles&#44; regardless of the participants&#180; age<span class="elsevierStyleSup">18</span>&#46; The discrepancy between our findings and the results of the systematic review by Hutchison et al&#46;<span class="elsevierStyleSup">3</span> can be explained by the fact that these authors pooled the results of studies involving different age groups&#46; When we controlled for this factor&#44; the statistical significance of the differences in the estimates disappeared&#46;</p><p class="elsevierStylePara">In accordance with the terminology proposed by Altman&#44;<span class="elsevierStyleSup">23</span> we present our results as estimates of the number needed to treat &#40;ie&#44; to vaccinate&#41; and the confidence interval&#46; We extrapolated our figures to the most plausible incidence of cases of invasive disease in the community<span class="elsevierStyleSup">50</span> &#173;50 per 100 000 persons aged 65 years or older&#173;assuming that 90&#37; of the cases are caused by one of the serotypes included in the vaccine&#46; The estimated NNT to prevent one case of invasive disease is 6947&#44; with a CI that includes&#44; on one extreme&#44; the chance of causing one case of invasive disease per 12 352 persons or more vaccinated&#44; and on the other extreme&#44; the chances of preventing one case per every 3644 or more persons vaccinated&#46; These estimates mean that we cannot claim to have sufficient evidence to support vaccination&#46; The actual estimate lies somewhere on a continuum of values that includes&#44; in addition to the null effect&#44; the possibility that vaccination itself might contribute to cases of the disease it is intended to prevent&#46;</p><p class="elsevierStylePara">In conclusion&#44; our review provides no proof that pneumococcal vaccination with nonconjugate capsular polysaccharide vaccines of <span class="elsevierStyleItalic">S&#46; pneumoniae</span> is effective in reducing or preventing pneumococcal disease in older persons&#46; In the light of the results of the present review and meta-analysis&#44; we can only conclude that the systematic recommendation for vaccination in the population of persons 65 years of age or older should not be made in the absence of results of clinical trials that unequivocally demonstrate a protective effect&#46;</p><hr></hr><p class="elsevierStylePara">Acknowledgments </p><hr></hr><p class="elsevierStylePara">We thank Dr&#46; Soledad M&#225;rquez Calder&#243;n of the Andalusia Public Health School&#44; Dr&#46; Juan B&#46; Bellido of the Epidemiolgy Section&#44; Castell&#243;n Public Health Center&#44; and Dr&#46; Vicente Palop of the Geriatrics Unit&#44; Internal Medicine Service&#44; Hospital de la Ribera in Alzira&#44; Valencia&#44; for their comments on and contributions to earlier versions of this manuscript&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Correspondence&#58; Joan Puig-Barber&#224;&#46; Avenida Ferrandis Salvador&#44; 50&#46; 12100 Castell&#243;n&#46; Espa&#241;a&#46; E-mail&#58; jpuig&#64;terra&#46;es</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Based on a talk given at the XXI Congress of the Spanish Society of Family and Community Medicine&#44; San Sebasti&#225;n&#44; 14-17 November 2001&#46;</p><p class="elsevierStylePara">Awarded First prize by the PAPPS-semFYM&#47;Almirall Prodesfarma at the XXI Congress of the Spanish Society of Family and Community Medicine&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"> Manuscript accepted for publication 20 February 2002&#46;</p>"
    "pdfFichero" => "27v30n05a13037691pdf001.pdf"
    "tienePdf" => true
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec692960"
          "palabras" => array:4 [
            0 => "Metaan&#225;lisis"
            1 => "Infecci&#243;n neumoc&#243;cica"
            2 => "Vacunaci&#243;n"
            3 => "Anciano"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec692959"
          "palabras" => array:4 [
            0 => "Meta-analysis"
            1 => "Pneumococcal infection"
            2 => "Vaccination"
            3 => "Aged"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:1 [
        "resumen" => "Aim&#46; Estimate pneumococcal vaccine effectiveness in preventing <span class="elsevierStyleItalic">Streptococcus pneumoniae </span>illness in the elderly&#46; Design&#46; Systematic review and meta-analysis&#46; Data source&#46; MEDLINE&#44; years 1964 to the 2000&#59; EMBASE&#44; from 1988 to the 2000&#59; Cochrane Library&#44; identified studies and previously published systematic reviews citations peruse&#44; and contacts with field experts&#46; Study selection&#46; Clinical trials&#44; cohort and case-control studies&#44; published in Spanish&#44; English or French&#44; that estimated pneumococcal disease rates in vaccinated <br /> or not vaccinated elderly&#46; Data extraction&#46; The studies were valued independently by four investigators with predefined criteria of validity&#44; such as results comparing rates of disease caused by serotypes included in the vaccine&#44; random allocation&#44; double blind design&#44; included subjects pertaining to the same study base&#44; and losses of less than 10&#37; in clinical trials and 20&#37; in observational studies&#46; Results&#46; Eight clinical trials considered the relative risk &#40;RR&#41; of pneumococcal pneumonia&#44; three did not make estimations on pneumonia originated by serotypes included in the vaccine and only one study fulfilled all the inclusion criteria&#46; Vaccinated versus not vaccinated pneumococcal pneumonia RR was 0&#46;86 &#40;95&#37; CI&#44; 0&#46;24 to 2&#46;99&#41;&#46; Vaccine effectiveness was 14&#37; &#40;95&#37; CI&#44; &#173;199 to 76&#37;&#41;&#46; Ten studies performed estimations on the effectiveness of the vaccine on invasive disease by vaccine serotypes&#46; Of these&#44; two clinical trials and two observational studies fulfilled the required quality criteria&#46; RR <br /> of invasive disease was of 0&#46;68 &#40;95&#37; CI&#44; 0&#46;39-1&#46;18&#41;&#59; vaccine effectiveness was 32&#37; &#40;95&#37; CI&#44; &#173;1861&#37;&#41;&#46; Conclusions&#46; No evidence was found supporting pneumococcal vaccine effectiveness to reduce or avoid <span class="elsevierStyleItalic">S&#46; pneumoniae </span>disease in the elderly&#46;"
      ]
      "es" => array:1 [
        "resumen" => "Objetivo&#46; Estimar la efectividad de la vacuna neumoc&#243;cica para evitar enfermedad por <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> en ancianos&#46; Dise&#241;o&#46; Revisi&#243;n sistem&#225;tica y metaan&#225;lisis&#46; Fuentes de datos&#46; MEDLINE&#44; a&#241;os 1964 a 2000&#59; EMBASE&#44; de 1988 a 2000&#59; Cochrane Library&#44; citas bibliogr&#225;ficas de estudios identificados&#44; revisiones sistem&#225;ticas anteriores y contactos con otros autores&#46; Selecci&#243;n de los estudios&#46; Ensayos cl&#237;nicos&#44; estudios de cohortes y de casos y controles&#44; publicados en castellano&#44; ingl&#233;s o franc&#233;s&#44; que estimaron tasas de enfermedad neumoc&#243;cica en ancianos vacunados y no vacunados&#46; Extracci&#243;n de datos&#46; Los estudios fueron valorados independientemente por 4 investigadores con criterios de validez predefinidos&#44; tales como realizar estimaciones de tasas de enfermedad por serotipos incluidos en la vacuna&#44; asignaci&#243;n aleatoria&#44; doble enmascaramiento&#44; pertenencia a una misma base del estudio de los sujetos incluidos y tasas de p&#233;rdida inferiores al 10&#37; en ensayos cl&#237;nicos y al 20&#37; en los estudios observacionales&#46; Resultados&#46; Ocho ensayos cl&#237;nicos estimaron el riesgo relativo &#40;RR&#41; de neumon&#237;a neumoc&#243;cica&#44; tres no realizaron estimaciones sobre neumon&#237;a originada por serotipos incluidos en la vacuna y s&#243;lo uno de los 8 cumpli&#243; los criterios de inclusi&#243;n&#46; El RR de neumon&#237;a neumoc&#243;cica de los vacunados&#44; frente a los no vacunados&#44; fue del 0&#44;86 &#40;intervalo de confianza &#91;IC&#93; del 95&#37;&#44; 0&#44;24 a 2&#44;99&#41;&#46; La efectividad de la vacuna fue del 14&#37; &#40;IC del 95&#37;&#44; &#173;199 al 76&#37;&#41;&#46; Diez estudios llevaron a cabo estimaciones de la efectividad de la vacuna sobre enfermedad invasora por serotipos incluidos en la vacuna&#46; De &#233;stos&#44; dos ensayos cl&#237;nicos y dos estudios observacionales reunieron los criterios de calidad requeridos&#46; El RR de enfermedad invasora fue de 0&#44;68 &#40;IC del 95&#37;&#44; 0&#44;39 a 1&#44;18&#41;&#46; La efectividad de la vacuna fue del 32&#37; &#40;IC del 95&#37;&#44; &#191;18 a 61&#37;&#41;&#46; Conclusiones&#46; No se encontraron pruebas de la efectividad de la vacuna neumoc&#243;cica para reducir o evitar la enfermedad neumoc&#243;cica en el anciano&#46;"
      ]
    ]
    "multimedia" => array:22 [
      0 => array:6 [
        "identificador" => "tbl1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab01.gif"
                  "imagenAlto" => 944
                  "imagenAncho" => 706
                  "imagenTamanyo" => 30881
                ]
              ]
            ]
          ]
        ]
      ]
      1 => array:6 [
        "identificador" => "tbl2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab02.gif"
                  "imagenAlto" => 202
                  "imagenAncho" => 353
                  "imagenTamanyo" => 7263
                ]
              ]
            ]
          ]
        ]
      ]
      2 => array:6 [
        "identificador" => "tbl3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab03.gif"
                  "imagenAlto" => 978
                  "imagenAncho" => 731
                  "imagenTamanyo" => 41751
                ]
              ]
            ]
          ]
        ]
      ]
      3 => array:6 [
        "identificador" => "tbl4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab04.gif"
                  "imagenAlto" => 887
                  "imagenAncho" => 733
                  "imagenTamanyo" => 43695
                ]
              ]
            ]
          ]
        ]
      ]
      4 => array:6 [
        "identificador" => "tbl5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab05.gif"
                  "imagenAlto" => 756
                  "imagenAncho" => 732
                  "imagenTamanyo" => 41057
                ]
              ]
            ]
          ]
        ]
      ]
      5 => array:6 [
        "identificador" => "tbl6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab06.gif"
                  "imagenAlto" => 730
                  "imagenAncho" => 735
                  "imagenTamanyo" => 38747
                ]
              ]
            ]
          ]
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl7"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab07.gif"
                  "imagenAlto" => 215
                  "imagenAncho" => 729
                  "imagenTamanyo" => 37892
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "Relative risks of pneumococcal pneumonia&#46; Part a shows all studies that measured the effectiveness of vaccination in preventing this disease&#59; the test for homogeneity yielded a chi-squared value of 191&#46;63 with 7 degrees of freedom and P &#60; &#46;001&#46; Part b shows that after the study by Kaufman et al&#46;25 was excluded&#44; the test for homogeneity yielded a chi-squared value of 2&#46;69 with 7 degrees of freedom and P &#60; &#46;85&#46; Part c shows the three studies that calculated the RR for pneumococcal pneumonia in vaccinated versus unvaccinated persons and that fulfilled our methodological quality criteria&#46; However&#44; two studies &#40;Davis et al&#46;36 and Ortqvist et al&#46;45&#41; failed to investigate the serotypes that caused the disease&#46; The areas of the boxes reflect the precision of the estimates obtained in different studies&#46;"
        ]
      ]
      7 => array:6 [
        "identificador" => "tbl8"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab08.gif"
                  "imagenAlto" => 237
                  "imagenAncho" => 725
                  "imagenTamanyo" => 11756
                ]
              ]
            ]
          ]
        ]
      ]
      8 => array:8 [
        "identificador" => "tbl9"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab09.gif"
                  "imagenAlto" => 373
                  "imagenAncho" => 730
                  "imagenTamanyo" => 32270
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "a&#41; Estimates of relative risk &#40;RR&#41; of invasive disease caused by the pneumococcal serotypes included in the vaccine and the 95&#37; confidence intervals &#40;95&#37; CI&#41;&#46; For all studies retrieved&#44; the test for homogeneity yielded a chi-squared value of 16&#46;12 with 9 degrees of freedom and P&#61;&#46;06&#46; The x axis scale has been truncated on both ends to improve legibility&#46; b&#41; Estimates of RR and 95&#37; CI for the studies that fulfilled our inclusion criteria&#46; Global RR was 0&#46;68&#44; 95&#37; CI was 0&#46;39 to 1&#46;18&#59; P&#61;&#46;17&#46; The test for homogeneity yielded a chi-squared value of 2&#46;09 with 3 degrees of freedom and P&#61;&#46;55&#46; The areas of the boxes reflect the precision of the estimates obtained in different studies&#46;"
        ]
      ]
      9 => array:8 [
        "identificador" => "tbl10"
        "etiqueta" => "Figura 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab10.gif"
                  "imagenAlto" => 505
                  "imagenAncho" => 730
                  "imagenTamanyo" => 41434
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "Results of metaregression analysis of the effect of publication bias on estimates of the effectiveness of vaccination in preventing invasive disease&#46; Estimates for studies classified as A or B were significantly different &#40;P&#61;&#46;004&#41; from estimates obtained for studies classified as C&#46; Interpretation of values along the x axis&#58; A&#44; A Low likelihood of bias&#59; B&#44; moderate likelihood of bias&#59; C&#44; high likelihood of bias &#40;see Methods section&#41;&#46;"
        ]
      ]
      10 => array:6 [
        "identificador" => "tbl11"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "27v30n05-13037691tab11.gif"
                  "imagenAlto" => 556
                  "imagenAncho" => 332
                  "imagenTamanyo" => 23016
                ]
              ]
            ]
          ]
        ]
      ]
      11 => array:5 [
        "identificador" => "tbl12"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      12 => array:5 [
        "identificador" => "tbl13"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      13 => array:5 [
        "identificador" => "tbl14"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      14 => array:5 [
        "identificador" => "tbl15"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      15 => array:5 [
        "identificador" => "tbl16"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      16 => array:5 [
        "identificador" => "tbl17"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      17 => array:5 [
        "identificador" => "tbl18"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      18 => array:5 [
        "identificador" => "tbl19"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      19 => array:5 [
        "identificador" => "tbl20"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      20 => array:5 [
        "identificador" => "tbl21"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
      21 => array:5 [
        "identificador" => "tbl22"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Bibliography"
      "seccion" => array:1 [
        0 => array:1 [
          "bibliografiaReferencia" => array:50 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Efficacy of pneumococcal vaccination in adults. A meta-analysis of randomized controlled trials. Arch Intern Med 1994;154:2666-77."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Efficacy of pneumococcal vaccination in adults&#46; A meta-analysis of randomized controlled trials&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Fine MJ"
                            1 => "Smith MA"
                            2 => "Carson CA"
                            3 => "Meffe F"
                            4 => "Sankey SS"
                            5 => "Weissfeld LA"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "1994"
                        "volumen" => "154"
                        "paginaInicial" => "2666"
                        "paginaFinal" => "77"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7993150"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997;46(RR-8):1-24."
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "CDC&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Clinical effectiveness of pneumococcal vaccine. Meta-analysis. Can Fam Physician 1999;45:2381-93."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Clinical effectiveness of pneumococcal vaccine&#46; Meta-analysis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Hutchison BG"
                            1 => "Oxman AD"
                            2 => "Shannon HS"
                            3 => "Lloyd S"
                            4 => "Altmayer CA"
                            5 => "Thomas K&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Can Fam Physician"
                        "fecha" => "1999"
                        "volumen" => "45"
                        "paginaInicial" => "2381"
                        "paginaFinal" => "93"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10540698"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Are the pneumococcal polysaccharide vaccines effective? Meta-analysis of the prospective trials. BMC Fam Pract 2000;1:1."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Are the pneumococcal polysaccharide vaccines effective&#63; Meta-analysis of the prospective trials&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Moore RA"
                            1 => "Wiffen PJ"
                            2 => "Lipsky BA&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1471-2296-1-1"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMC Fam Pract"
                        "fecha" => "2000"
                        "volumen" => "1"
                        "paginaInicial" => "1"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11038265"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Informe sobre la vacuna neumocócica. Med Clin (Barc) 1994;102:383-6."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Informe sobre la vacuna neumoc&#243;cica&#46;"
                      "idioma" => "es"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Subdirecci&#243;n General de Prestaciones y Evaluaci&#243;n de Tecnolog&#237;as Sanitaria&#46;s"
                            1 => "Ministerio de Sanidad y Consumo&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Med Clin (Barc)"
                        "fecha" => "1994"
                        "volumen" => "102"
                        "paginaInicial" => "383"
                        "paginaFinal" => "6"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Actividades preventivas en atención primaria: identificación de áreas de concordancia entre guías de práctica clínica basadas en la evidencia. Med Clin (Barc) 2000;114(Supl 2):88-92."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Actividades preventivas en atenci&#243;n primaria&#58; identificaci&#243;n de &#225;reas de concordancia entre gu&#237;as de pr&#225;ctica cl&#237;nica basadas en la evidencia&#46;"
                      "idioma" => "es"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Gosalbes-Soler V"
                            1 => "M&#225;rquez-Calder&#243;n S"
                            2 => "Maiques-Gal&#225;n A"
                            3 => "LatourP&#233;rez J"
                            4 => "Bernal-Delgado E"
                            5 => "Puig-Barber&#224; J"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Med Clin (Barc)"
                        "fecha" => "2000"
                        "volumen" => "114"
                        "paginaInicial" => "88"
                        "paginaFinal" => "92"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Surveillance of pneumococcal infection for field trials of polyvalent pneumococcal vaccines. DAB-VDP-12-84, 1-84. 1980 [ref. type: report]. Bethesda (MD), National Institute of Health."
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Austrian R&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Resolving the pneumococcal vaccine controversy: are there alternatives to randomized clinical trials? Rev Infect Dis 1984;6:589-600."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Resolving the pneumococcal vaccine controversy&#58; are there alternatives to randomized clinical trials&#63;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Clemens JD"
                            1 => "Shapiro ED&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Infect Dis"
                        "fecha" => "1984"
                        "volumen" => "6"
                        "paginaInicial" => "589"
                        "paginaFinal" => "600"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6390636"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Oxford: Update Software, 2001."
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "The Cochrane Librar&#46;y"
                            1 => "Issue 1"
                            2 => "Updated quarterly&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Methodology and reports of systematic reviews and meta-analyses: a comparison of Cochrane reviews with articles published in paper-based journals. JAMA 1998;280:278-80."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Methodology and reports of systematic reviews and meta-analyses&#58; a comparison of Cochrane reviews with articles published in paper-based journals&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Jadad AR"
                            1 => "Cook DJ"
                            2 => "Jones A"
                            3 => "Klassen TP"
                            4 => "Tugwell P"
                            5 => "Moher M"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1998"
                        "volumen" => "280"
                        "paginaInicial" => "278"
                        "paginaFinal" => "80"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9676681"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses. Lancet 1999;354:1896-900."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Improving the quality of reports of meta-analyses of randomised controlled trials&#58; the QUOROM statement&#46; Quality of reporting of meta-analyses&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Moher D"
                            1 => "Cook DJ"
                            2 => "Eastwood S"
                            3 => "Olkin I"
                            4 => "Rennie D"
                            5 => "Stroup DF&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1999"
                        "volumen" => "354"
                        "paginaInicial" => "1896"
                        "paginaFinal" => "900"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10584742"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Cochrane Reviewers' Handbook 4.0 [updated July 1999]. The Cochrane Library [database on CDROM]. The Cochrane Collaboration. Oxford: Update Software, 2000."
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Clarke M"
                            1 => "Oxman AD"
                            2 => "editors&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008-12."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Meta-analysis of observational studies in epidemiology&#58; a proposal for reporting&#46; Meta-analysis Of Observational Studies in Epidemiology &#40;MOOSE&#41; group&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Stroup DF"
                            1 => "Berlin JA"
                            2 => "Morton SC"
                            3 => "Olkin I"
                            4 => "Williamson GD"
                            5 => "Rennie D"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2000"
                        "volumen" => "283"
                        "paginaInicial" => "2008"
                        "paginaFinal" => "12"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10789670"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The «case-control» study: valid selection of subjects. J Chronic Dis 1985;38:543-8."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The &#171;case-control&#187; study&#58; valid selection of subjects&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Miettinen OS&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Chronic Dis"
                        "fecha" => "1985"
                        "volumen" => "38"
                        "paginaInicial" => "543"
                        "paginaFinal" => "8"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4008595"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-12."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Empirical evidence of bias&#46; Dimensions of methodological quality associated with estimates of treatment effects in controlled trials&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Schulz KF"
                            1 => "Chalmers I"
                            2 => "Hayes RJ"
                            3 => "Altman DG&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1995"
                        "volumen" => "273"
                        "paginaInicial" => "408"
                        "paginaFinal" => "12"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7823387"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Evidence-based medicine. How to practice and teach EBM. 2nd ed. London: Churchill Livingstone, 2000."
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Sackett DL"
                            1 => "Strauss SE"
                            2 => "Richardson WS"
                            3 => "Rosenberg W"
                            4 => "Haynes RB&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The importance of quality of primary studies in producing unbiased systematic reviews. Arch Intern Med 1996;156:661-6."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The importance of quality of primary studies in producing unbiased systematic reviews&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Khan KS"
                            1 => "Daya S"
                            2 => "Jadad A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "1996"
                        "volumen" => "156"
                        "paginaInicial" => "661"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8629879"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Meta-analysis in clinical trials&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "DerSimonian R"
                            1 => "Laird N&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Control Clin Trials"
                        "fecha" => "1986"
                        "volumen" => "7"
                        "paginaInicial" => "177"
                        "paginaFinal" => "88"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3802833"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Bias in meta-analysis detected by a simple&#44; graphical test&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Egger M"
                            1 => "Davey SG"
                            2 => "Schneider M"
                            3 => "Minder C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "1997"
                        "volumen" => "315"
                        "paginaInicial" => "629"
                        "paginaFinal" => "34"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9310563"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "sbe23: meta-analysis regression. Stata Tech Bull 1998;42:16-24."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "sbe23&#58; meta-analysis regression&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Sharp S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Stata Tech Bull"
                        "fecha" => "1998"
                        "volumen" => "42"
                        "paginaInicial" => "16"
                        "paginaFinal" => "24"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Proportion of disease caused or prevented by a given exposure, trait or intervention. Am J Epidemiol 1974;99: 325-32."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Proportion of disease caused or prevented by a given exposure&#44; trait or intervention&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Miettinen OS&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Epidemiol"
                        "fecha" => "1974"
                        "volumen" => "99"
                        "paginaInicial" => "325"
                        "paginaFinal" => "32"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4825599"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318:1728-33."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "An assessment of clinically useful measures of the consequences of treatment&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Laupacis A"
                            1 => "Sackett DL"
                            2 => "Roberts RS&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM198806303182605"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1988"
                        "volumen" => "318"
                        "paginaInicial" => "1728"
                        "paginaFinal" => "33"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3374545"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Confidence intervals for the number needed to treat. BMJ 1998;317:1309-12."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Confidence intervals for the number needed to treat&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Altman DG&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "1998"
                        "volumen" => "317"
                        "paginaInicial" => "1309"
                        "paginaFinal" => "12"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9804726"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides. J Exp Med 1945;82:445-65."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "MacLeod CM"
                            1 => "Hodges RG"
                            2 => "Heidelberg M"
                            3 => "Bernhard WG&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Exp Med"
                        "fecha" => "1945"
                        "volumen" => "82"
                        "paginaInicial" => "445"
                        "paginaFinal" => "65"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19871511"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Pneumonia in old age: active immunization against pneumonia with pneumococcus polysaccharide-results of a six year study. Arch Intern Med 1947;79:518-31."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pneumonia in old age&#58; active immunization against pneumonia with pneumococcus polysaccharide-results of a six year study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Kaufman P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "1947"
                        "volumen" => "79"
                        "paginaInicial" => "518"
                        "paginaFinal" => "31"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Immunisation with a polyvalent pneumococcal vaccine. Reduction of adult respiratory mortality in a New Guinea Highlands community. Lancet 1977;1:1338-41."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Immunisation with a polyvalent pneumococcal vaccine&#46; Reduction of adult respiratory mortality in a New Guinea Highlands community&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Riley ID"
                            1 => "Tarr PI"
                            2 => "Andrews M"
                            3 => "Pfeiffer M"
                            4 => "Howard R"
                            5 => "Challands P"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1977"
                        "volumen" => "1"
                        "paginaInicial" => "1338"
                        "paginaFinal" => "41"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2566875"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Protective efficacy of pneumococcal polysaccharide vaccines. JAMA 1977;238:2613-6."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Protective efficacy of pneumococcal polysaccharide vaccines&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Smit P"
                            1 => "Oberholzer D"
                            2 => "Hayden-Smith S"
                            3 => "Koornhof HJ"
                            4 => "Hilleman MR&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1977"
                        "volumen" => "238"
                        "paginaInicial" => "2613"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21973"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Prevention of pneumococcal infection by immunization with capsular polysaccharides of Streptococcus pneumoniae: current status of polyvalent vaccines. J Infect Dis 1977; 136(Suppl 1):38-42."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Prevention of pneumococcal infection by immunization with capsular polysaccharides of Streptococcus pneumoniae&#58; current status of polyvalent vaccines&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Austrian R&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Infect Dis"
                        "fecha" => "1977"
                        "volumen" => "136"
                        "paginaInicial" => "38"
                        "paginaFinal" => "42"
                        "itemHostRev" => array:3 [
                          "pii" => "S0266613813003069"
                          "estado" => "S300"
                          "issn" => "02666138"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Pneumococcal vaccine in the institutionalized elderly: design of a nonrandomized trial and preliminary results. Rev Infect Dis 1981;3(Suppl):71-81."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pneumococcal vaccine in the institutionalized elderly&#58; design of a nonrandomized trial and preliminary results&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Bentley DW"
                            1 => "Ha K"
                            2 => "Mamot K"
                            3 => "Moon D"
                            4 => "Moore L"
                            5 => "Poletto P"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rev Infect Dis"
                        "fecha" => "1981"
                        "volumen" => "3"
                        "paginaInicial" => "71"
                        "paginaFinal" => "81"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections. Ann Intern Med 1984; 101:325-30."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Shapiro ED"
                            1 => "Clemens JD&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Intern Med"
                        "fecha" => "1984"
                        "volumen" => "101"
                        "paginaInicial" => "325"
                        "paginaFinal" => "30"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6380367"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Essai clinique du vaccin antipneumococcique chez des personnes agees vivant en institution. Rev Epidemiol Sante Publique 1985;33:437-44."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Essai clinique du vaccin antipneumococcique chez des personnes agees vivant en institution&#46;"
                      "idioma" => "fr"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Gaillat J"
                            1 => "Zmirou D"
                            2 => "Mallaret MR"
                            3 => "Rouhan D"
                            4 => "Bru JP"
                            5 => "Stahl JP"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Epidemiol Sante Publique"
                        "fecha" => "1985"
                        "volumen" => "33"
                        "paginaInicial" => "437"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3914014"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib32"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Pneumococcal vaccine efficacy in selected populations in the United States. Ann Intern Med 1986;104:1-6."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pneumococcal vaccine efficacy in selected populations in the United States&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Bolan G"
                            1 => "Broome CV"
                            2 => "Facklam RR"
                            3 => "Plikaytis BD"
                            4 => "Fraser DW"
                            5 => "Schlech WF&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Intern Med"
                        "fecha" => "1986"
                        "volumen" => "104"
                        "paginaInicial" => "1"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3940476"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib33"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Placebo controlled pneumococcal immunization in patients with bronchogenic carcinoma. Eur J Cancer Clin Oncol 1986;22:807-13."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Placebo controlled pneumococcal immunization in patients with bronchogenic carcinoma&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Klastersky J"
                            1 => "Mommen P"
                            2 => "Cantraine F"
                            3 => "Safary A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Cancer Clin Oncol"
                        "fecha" => "1986"
                        "volumen" => "22"
                        "paginaInicial" => "807"
                        "paginaFinal" => "13"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3770039"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib34"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Pneumococcal vaccine prevents death from acute lower-respiratory-tract infections in Papua New Guinean children. Lancet 1986;2:877-81."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pneumococcal vaccine prevents death from acute lower-respiratory-tract infections in Papua New Guinean children&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Riley ID"
                            1 => "Lehmann D"
                            2 => "Alpers MP"
                            3 => "Marshall TF"
                            4 => "Gratten H"
                            5 => "Smith D&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2215-0366(15)00422-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1986"
                        "volumen" => "2"
                        "paginaInicial" => "877"
                        "paginaFinal" => "81"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26462224"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib35"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;315:1318-27."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Efficacy of pneumococcal vaccine in high-risk patients&#46; Results of a Veterans Administration Cooperative Study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Simberkoff MS"
                            1 => "Cross AP"
                            2 => "Al IM"
                            3 => "Baltch AL"
                            4 => "Geiseler PJ"
                            5 => "Nadler J"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM198611203152104"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1986"
                        "volumen" => "315"
                        "paginaInicial" => "1318"
                        "paginaFinal" => "27"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3534568"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib36"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Pneumococcal infection and immunologic response to pneumococcal vaccine in chronic obstructive pulmonary disease. A pilot study. Chest 1987;92:204-12."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pneumococcal infection and immunologic response to pneumococcal vaccine in chronic obstructive pulmonary disease&#46; A pilot study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Davis AL"
                            1 => "Aranda CP"
                            2 => "Schiffman G"
                            3 => "Christianson LC&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Chest"
                        "fecha" => "1987"
                        "volumen" => "92"
                        "paginaInicial" => "204"
                        "paginaFinal" => "12"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3608590"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0266613807000150"
                          "estado" => "S300"
                          "issn" => "02666138"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib37"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Inefficacy of pneumococcal vaccine in a high-risk population. Am J Med 1987; 83:425-30."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Inefficacy of pneumococcal vaccine in a high-risk population&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Forrester HL"
                            1 => "Jahnigen DW"
                            2 => "LaForce FM&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Med"
                        "fecha" => "1987"
                        "volumen" => "83"
                        "paginaInicial" => "425"
                        "paginaFinal" => "30"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3661581"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib38"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease. CMAJ 1987;136:361-5."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Leech JA"
                            1 => "Gervais A"
                            2 => "Ruben FL&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "CMAJ"
                        "fecha" => "1987"
                        "volumen" => "136"
                        "paginaInicial" => "361"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3545418"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib39"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med 1988;108:653-7."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The clinical effectiveness of pneumococcal vaccine in the elderly&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Sims RV"
                            1 => "Steinmann WC"
                            2 => "McConville JH"
                            3 => "King LR"
                            4 => "Zwick WC"
                            5 => "Schwartz JS&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Intern Med"
                        "fecha" => "1988"
                        "volumen" => "108"
                        "paginaInicial" => "653"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3358567"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib40"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Pneumococcal vaccine. Efficacy and associated cost savings. JAMA 1990;264:2910-5."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pneumococcal vaccine&#46; Efficacy and associated cost savings&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Gable CB"
                            1 => "Holzer SS"
                            2 => "Engelhart L"
                            3 => "Friedman RB"
                            4 => "Smeltz F"
                            5 => "Schroeder D"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1990"
                        "volumen" => "264"
                        "paginaInicial" => "2910"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2232086"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib41"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991;325: 1453-60."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The protective efficacy of polyvalent pneumococcal polysaccharide vaccine&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Shapiro ED"
                            1 => "Berg AT"
                            2 => "Austrian R"
                            3 => "Schroeder D"
                            4 => "Parcells V"
                            5 => "Margolis A"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199111213252101"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1991"
                        "volumen" => "325"
                        "paginaInicial" => "1453"
                        "paginaFinal" => "60"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1944423"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib42"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Pneumococcal polysaccharide vaccine efficacy. An evaluation of current recommendations. JAMA 1993;270:1826-31."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pneumococcal polysaccharide vaccine efficacy&#46; An evaluation of current recommendations&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Butler JC"
                            1 => "Breiman RF"
                            2 => "Campbell JF"
                            3 => "Lipman HB"
                            4 => "Broome CV"
                            5 => "Facklam RR&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "1993"
                        "volumen" => "270"
                        "paginaInicial" => "1826"
                        "paginaFinal" => "31"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8411526"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib43"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Preventing pneumococcal bacteremia in patients at risk. Results of a matched case-control study. Arch Intern Med 1995;155:2336-40."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Preventing pneumococcal bacteremia in patients at risk&#46; Results of a matched case-control study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Farr BM"
                            1 => "Johnston BL"
                            2 => "Cobb DK"
                            3 => "Fisch MJ"
                            4 => "Germanson TP"
                            5 => "Adal KA"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "1995"
                        "volumen" => "155"
                        "paginaInicial" => "2336"
                        "paginaFinal" => "40"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7487259"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib44"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial. Am J Med 1997;103:281-90."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Clinical efficacy of pneumococcal vaccine in the elderly&#58; a randomized&#44; single-blind population-based trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Koivula I"
                            1 => "Sten M"
                            2 => "Leinonen M"
                            3 => "Makela PH&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Med"
                        "fecha" => "1997"
                        "volumen" => "103"
                        "paginaInicial" => "281"
                        "paginaFinal" => "90"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9382120"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib45"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet 1998;351:399-403."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people&#46; Swedish Pneumococcal Vaccination Study Group&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Ortqvist A"
                            1 => "Hedlund J"
                            2 => "Burman LA"
                            3 => "Elbel E"
                            4 => "Hofer M"
                            5 => "Leinonen M"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1998"
                        "volumen" => "351"
                        "paginaInicial" => "399"
                        "paginaFinal" => "403"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9482293"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib46"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older. Vaccine 1999;17:2493-500."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Honkanen PO"
                            1 => "Keistinen T"
                            2 => "Miettinen L"
                            3 => "Herva E"
                            4 => "Sankilampi U"
                            5 => "Laara E"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Vaccine"
                        "fecha" => "1999"
                        "volumen" => "17"
                        "paginaInicial" => "2493"
                        "paginaFinal" => "500"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10418894"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib47"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease. Arch Intern Med 2000;159:2437-42."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Nichol KL"
                            1 => "Baken L"
                            2 => "Wuorenna J"
                            3 => "Nelson A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "2000"
                        "volumen" => "159"
                        "paginaInicial" => "2437"
                        "paginaFinal" => "42"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10665892"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib48"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342:1878-86."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A comparison of observational studies and randomized&#44; controlled trials&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Benson K"
                            1 => "Hartz AJ&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM200006223422506"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2000"
                        "volumen" => "342"
                        "paginaInicial" => "1878"
                        "paginaFinal" => "86"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10861324"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib49"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887-92."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Randomized&#44; controlled trials&#44; observational studies&#44; and the hierarchy of research designs&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Concato J"
                            1 => "Shah N"
                            2 => "Horwitz RI&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM200006223422507"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2000"
                        "volumen" => "342"
                        "paginaInicial" => "1887"
                        "paginaFinal" => "92"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10861325"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib50"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Epidemiology of invasive Streptococcus pneumoniae infections in the United States, 1995-1998: opportunities for prevention in the conjugate vaccine era. JAMA 2001; 285:1729-35."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Epidemiology of invasive Streptococcus pneumoniae infections in the United States&#44; 1995-1998&#58; opportunities for prevention in the conjugate vaccine era&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Robinson KA"
                            1 => "Baughman W"
                            2 => "Rothrock G"
                            3 => "Barrett NL"
                            4 => "Pass M"
                            5 => "Lexau C"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2001"
                        "volumen" => "285"
                        "paginaInicial" => "1729"
                        "paginaFinal" => "35"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11277827"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/02126567/0000003000000005/v0_201607121036/13037691/v0_201607121036/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "14695"
    "tipo" => "SECCION"
    "es" => array:2 [
      "titulo" => "Originales"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "es"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/02126567/0000003000000005/v0_201607121036/13037691/v0_201607121036/en/27v30n05a13037691pdf001.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13037691?idApp=UINPBA00004N"
]

Article information

ISSN: 02126567
Original language: English

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	1	0	1
2024 October	33	7	40
2024 September	50	19	69
2024 August	35	17	52
2024 July	26	5	31
2024 June	25	7	32
2024 May	26	8	34
2024 April	32	2	34
2024 March	39	5	44
2024 February	46	8	54
2024 January	88	10	98
2023 December	76	12	88
2023 November	61	12	73
2023 October	80	16	96
2023 September	24	7	31
2023 August	25	11	36
2023 July	45	10	55
2023 June	48	3	51
2023 May	63	7	70
2023 April	41	5	46
2023 March	52	7	59
2023 February	35	10	45
2023 January	21	3	24
2022 December	25	5	30
2022 November	11	9	20
2022 October	38	9	47
2022 September	30	11	41
2022 August	50	10	60
2022 July	26	7	33
2022 June	28	14	42
2022 May	51	3	54
2022 April	51	12	63
2022 March	67	8	75
2022 February	40	8	48
2022 January	43	11	54
2021 December	50	7	57
2021 November	50	11	61
2021 October	70	13	83
2021 September	35	25	60
2021 August	40	8	48
2021 July	33	9	42
2021 June	22	7	29
2021 May	34	10	44
2021 April	78	7	85
2021 March	44	11	55
2021 February	23	7	30
2021 January	27	10	37
2020 December	34	6	40
2020 November	31	4	35
2020 October	21	7	28
2020 September	26	13	39
2020 August	25	6	31
2020 July	22	3	25
2020 June	25	8	33
2020 May	36	6	42
2020 April	22	10	32
2020 March	25	8	33
2020 February	39	10	49
2020 January	33	5	38
2019 December	36	12	48
2019 November	26	12	38
2019 October	31	9	40
2019 September	43	9	52
2019 August	24	10	34
2019 July	33	12	45
2019 June	61	17	78
2019 May	164	23	187
2019 April	66	19	85
2019 March	32	18	50
2019 February	26	85	111
2019 January	13	37	50
2018 December	19	20	39
2018 November	32	32	64
2018 October	18	10	28
2018 September	23	8	31
2018 August	7	3	10
2018 July	9	1	10
2018 June	8	5	13
2018 May	5	10	15
2018 April	8	10	18
2018 March	8	0	8
2018 February	24	0	24
2018 January	3	1	4
2017 December	27	0	27
2017 November	8	0	8
2017 October	18	1	19
2017 September	5	12	17
2017 August	18	2	20
2017 July	16	2	18
2017 June	17	20	37
2017 May	37	5	42
2017 April	32	3	35
2017 March	26	39	65
2017 February	14	1	15
2017 January	13	1	14
2016 December	23	6	29
2016 November	33	3	36
2016 October	55	7	62
2016 September	38	0	38
2016 August	19	2	21
2016 July	27	6	33
2016 June	33	12	45
2016 May	30	8	38
2016 April	7	2	9
2016 March	21	5	26
2016 February	21	10	31
2016 January	22	3	25
2015 December	29	4	33
2015 November	27	4	31
2015 October	18	4	22
2015 September	31	6	37
2015 August	39	4	43
2015 July	42	1	43
2015 June	18	0	18
2015 May	21	1	22
2015 April	29	5	34
2015 March	27	5	32
2015 February	13	2	15
2015 January	29	2	31
2014 December	73	6	79
2014 November	24	1	25
2014 October	43	3	46
2014 September	32	0	32
2014 August	21	2	23
2014 July	34	3	37
2014 June	30	3	33
2014 May	24	1	25
2014 April	21	0	21
2014 March	23	3	26
2014 February	17	2	19
2014 January	20	2	22
2013 December	21	2	23
2013 November	24	4	28
2013 October	30	2	32
2013 September	29	5	34
2013 August	24	4	28
2013 July	17	1	18
2002 September	1062	0	1062

Show all

Indexed in:

Follow us:

Subscribe:

Statistics

Indexed in:

Follow us:

Subscribe:

Statistics

Subscribe to our newsletter