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Indirect effects of paediatric conjugate vaccines on invasive pneumococcal disease in older adults

  • Pilar Ciruela
    Correspondence
    Corresponding author at: Agència de Salut Pública de Catalunya, Generalitat de Catalunya, C/Roc Boronat, 81–95, 08005 Barcelona, Spain.
    Affiliations
    Agència de Salut Pública de Catalunya, Generalitat de Catalunya, C/Roc Boronat, 81–95, 08005 Barcelona, Spain

    CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, C/Monforte de Lemos, 3–5, 28029 Madrid, Spain
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  • Sonia Broner
    Affiliations
    Agència de Salut Pública de Catalunya, Generalitat de Catalunya, C/Roc Boronat, 81–95, 08005 Barcelona, Spain
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  • Conchita Izquierdo
    Affiliations
    Agència de Salut Pública de Catalunya, Generalitat de Catalunya, C/Roc Boronat, 81–95, 08005 Barcelona, Spain
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  • Roman Pallarés
    Affiliations
    Hospital Universitari Bellvitge, Universitat de Barcelona, C/Feixa Llarga s/n 08907, L’Hospitalet, Barcelona, Spain

    CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/Monforte de Lemos, 3–5, 28029 Madrid, Spain
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  • Carmen Muñoz-Almagro
    Affiliations
    CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, C/Monforte de Lemos, 3–5, 28029 Madrid, Spain

    Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu 2, 08950 Esplugues, Barcelona, Spain

    Department of Medicine, Universitat Internacional de Catalunya, C/Josep Trueta, s/n 08195 Sant Cugat del Vallès, Barcelona, Spain
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  • Sergi Hernández
    Affiliations
    Agència de Salut Pública de Catalunya, Generalitat de Catalunya, C/Roc Boronat, 81–95, 08005 Barcelona, Spain
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  • Imma Grau
    Affiliations
    Hospital Universitari Bellvitge, Universitat de Barcelona, C/Feixa Llarga s/n 08907, L’Hospitalet, Barcelona, Spain

    CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/Monforte de Lemos, 3–5, 28029 Madrid, Spain
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  • Angela Domínguez
    Affiliations
    CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, C/Monforte de Lemos, 3–5, 28029 Madrid, Spain

    Departament de Medicina, Universitat de Barcelona, C/Casanova, 143, 08036 Barcelona, Spain
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  • Mireia Jané
    Affiliations
    Agència de Salut Pública de Catalunya, Generalitat de Catalunya, C/Roc Boronat, 81–95, 08005 Barcelona, Spain

    CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, C/Monforte de Lemos, 3–5, 28029 Madrid, Spain
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  • Author Footnotes
    1 The Catalan Working Group on Invasive Pneumococcal Disease: Cristina Esteva, Departament de Microbiologia Molecular, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Mariona Fernández de Sevilla, Servei de Pediatria, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Desiree Henares, Departament de Microbiologia Molecular, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Carmen Ardanuy, Hospital Universitari de Bellvitge, Universitat de Barcelona, C/Feixa Llarga s/n, 08907 L’Hospitalet, Barcelona, Spain. Francesc Marco, Servei de Microbiologia, Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona, Spain. Nuria Margall, Servei de Microbiologia, Hospital Santa Creu i Sant Pau, C/de Sant Quintí, 89, 08041 Barcelona, Spain. Araceli González-Cuevas, Laboratori de Microbiologia, Hospital General del Parc Sanitari Sant Joan de Déu, Camí Vell de la Colònia, 25, 08830 Sant Boi de Llobregat, Barcelona, Spain. Alvaro Díaz, Servei de Pediatria i Recerca, Fundació Hospital de Nens de Barcelona, C/Consell de Cent, 437, 08009 Barcelona, Spain. Maria Teresa Martin, Servei de Microbiologia, Hospital Universitari Vall d’Hebron, Pg. De la Vall d’Hebron, 119–129, 08035 Barcelona, Spain. Jaume Llaberia, Laboratori de Microbiologia, SCIAS Hospital de Barcelona, C/Diagonal, 660, 08034 Barcelona, Spain. Margarida Curriu, Servei de Microbiologia, Hospital Sant Bernabé, Ctra. de Ribes, s/n, 08600 Berga, Spain. Carme Gallés, Unitat de Microbiologia, Servei d'Anàlisis Clíniques, Corporació de Salut del Maresme i la Selva, C/Sant Jaume, 209–217, 08370 Calella, Barcelona, Spain. Elisenda Capdevila, Unitat de Microbiologia, Servei d'Anàlisis Clíniques, Corporació de Salut del Maresme i la Selva, C/Sant Jaume, 209–217, 08370 Calella, Barcelona, Spain. Paula Gassiot, Àrea de Microbiologia, Laboratori d’Anàlisis Clíniques, Hospital de Figueres, Rda. Rector Arolas, s/n, 17600 Figueres, Girona, Spain. Matilde Martínez-Zurita, Àrea de Microbiologia, Laboratori Clínic - Institut Català de la Salut Girona, Hospital Universitari Dr. Josep Trueta, Av. França, s/n, 17007 Girona, Spain. Carmina Martí, Laboratori de Microbiologia, Hospital General de Granollers, Av. Francesc Ribas, s/n, 08402 Granollers, Barcelona, Spain. Montserrat Morta, Servei de Microbiologia, Hospital Sant Joan de Déu, Fundació ALTHAIA, C/Dr. Joan Soler, s/n, 08243 Manresa, Barcelona, Spain. Goretti Sauca, Servei d’Análisis Clíniques, Secció de Microbiologia, Hospital de Mataró, Ctra. de Cirera, 230, 08304 Mataró, Barcelona, Spain. Asunción Gassós, Servei de Microbiologia, Sant Joan de Déu de Martorell, Av. Mancomunitats Comarcals, 1–3, 08760 Martorell, Barcelona, Spain. Esther Sanfeliu, Servei d’Anàlisis Clíniques, Secció de Microbiologia, Hospital d’Olot Comarcal de la Garrotxa, Av. dels Països Catalans, 86, 17800 Olot, Girona, Spain. Frederic Ballester, Laboratori de Referencia Sud, Hospital Sant Joan de Reus, Av. Dr Josep Laporte, 2, 43204 Reus, Tarragona, Spain. Isabel Pujol, Laboratori de Referencia Sud, Hospital Sant Joan de Reus, Av. Dr Josep Laporte, 2, 43204 Reus, Tarragona, Spain. Montserrat Olsina, Laboratori d’Anàlisis Clínics, Microbiologia, Hospital General de Catalunya, C/Pedro i Pons, 1, 08190 Sant Cugat del Vallès, Barcelona, Spain. Xavier Raga, Laboratori de Microbiologia, Hospital Sant Pau i Santa Tecla, Rambla Vella, 14, 43003 Tarragona, Spain. Frederic Gómez-Bertomeu, Àrea de Microbiologia, Laboratori Clínic ICS - Camp de Tarragona, Hospital Joan XXIII, C/Dr. Mallafrè Guasch, 4, 43005 Tarragona, Spain. Mar Olga Pérez-Moreno, Àrea de Microbiologia, Laboratori Clínic ICS - Terres de l’Ebre, Hospital Verge de la Cinta, C/de les Esplanetes, 14, 43500 Tortosa, Tarragona, Spain. Anna Vilamala, Servei de Microbiologia, Consorci Hospitalari de Vic, C/Francesc Pla 'El Vigatà', 1, 08500 Vic, Barcelona, Spain. Maria Navarro, Servei de Microbiologia, Consorci Hospitalari de Vic, C/Francesc Pla ‘El Vigatà’, 1, 08500 Vic, Barcelona, Spain. Mercè Ribelles, Secció Microbiologia, Servei d'Anàlisis Clíniques, Hospital Universitari Arnau de Vilanova de Lleida, Av. Rovira Roure, 80, 25198 Lleida, Barcelona, Spain. Mercè Garcia, Secció Microbiologia, Servei d'Anàlisis Clíniques, Hospital Universitari Arnau de Vilanova de Lleida, Av. Rovira Roure, 80, 25198 Lleida, Barcelona, Spain. Eduardo Padilla, Laboratori de Referència Catalunya, C/de la Selva, 10, 08820 Prat de Llobregat (El), Barcelona, Spain. Nuria Prim, Laboratori de Referència Catalunya, C/de la Selva, 10, 08820 Prat de Llobregat (El), Barcelona, Spain. Dionisia Fontanals, Secció de Microbiologia, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, UAB, C/Parc del Taulí, 1, 08208 Sabadell, Barcelona, Spain. Isabel Sanfeliu, Secció de Microbiologia, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, UAB C/Parc del Taulí, 1, 08208 Sabadell, Barcelona, Spain. Miguel Angel Benítez, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n, 08720 Vilafranca del Penedès, Barcelona, Spain. Eulalia Jou, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n, 08720 Vilafranca del Penedès, Barcelona, Spain. Carmina Sanjosé, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n 08720 Vilafranca del Penedès, Barcelona, Spain. Montserrat Giménez, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Ctra. de Canyet, s/n 08916 Badalona, Barcelona, Spain. Maria Dolores Quesada, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Ctra. de Canyet, s/n 08916 Badalona, Barcelona, Spain. Jose Carlos de la Fuente, Servei de Microbiologia, Hospital Comarcal Móra d’Ebre, C/de Benet Messeguer, s/n 43770 Móra d'Ebre, Tarragona, Spain. Ana Calderon, Servei de Microbiologia, Hospital Municipal de Badalona, C/Via Augusta, 9–13, 08911 Badalona, Barcelona, Spain. Percy Juan Ayala, Servei de Microbiologia, Clínica Terres de l’Ebre, Pl. De Joaquim Bau, 6–8, 43500 Tortosa, Tarragona, Spain. Josefa Pérez-Jové, Departament de Microbiologia, Catlab - Centre Analítiques Terrassa, AIE, Parc Logístic de Salut, Vial Sant Jordi, s/n, 08232 Viladecavalls, Barcelona, Spain. Ana Blanco, Departament de Microbiologia, Catlab - Centre Analítiques Terrassa, AIE, Parc Logístic de Salut, Vial Sant Jordi, s/n 08232, Viladecavalls, Barcelona, Spain. Conchita Balado, Departament de Microbiologia Clínica, Laboratori d’Anàlisis Dr. F Echevarne, C/de los Castillejos, 365, 08025 Barcelona, Spain. Ines Valle, Departament de Microbiologia Clínica, Laboratori d’Anàlisis Dr. F Echevarne, C/de los Castillejos, 365, 08025 Barcelona, Spain. Maria Teresa Bastida, Laboratori de Microbiologia, Fundació Hospital Esperit Sant, C/Pons i Rabadà s/n, 08923 Santa Coloma de Gramenet, Spain. Olga Gonzalez-Moreno, Laboratori de Microbiologia, SYNLAB Diagnósticos Globales S.A.U., C/Verge de Guadalupe, 18, 08950 Esplugues de Llobregat, Spain. Amaia Oteiza Ubanell, Laboratori d’Anàlisis Clíniques, Hospital de Palamós, C/Hospital, 36, 17230 Palamós, Spain.
    The Catalan Working Group on Invasive Pneumococcal Disease
    Footnotes
    1 The Catalan Working Group on Invasive Pneumococcal Disease: Cristina Esteva, Departament de Microbiologia Molecular, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Mariona Fernández de Sevilla, Servei de Pediatria, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Desiree Henares, Departament de Microbiologia Molecular, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Carmen Ardanuy, Hospital Universitari de Bellvitge, Universitat de Barcelona, C/Feixa Llarga s/n, 08907 L’Hospitalet, Barcelona, Spain. Francesc Marco, Servei de Microbiologia, Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona, Spain. Nuria Margall, Servei de Microbiologia, Hospital Santa Creu i Sant Pau, C/de Sant Quintí, 89, 08041 Barcelona, Spain. Araceli González-Cuevas, Laboratori de Microbiologia, Hospital General del Parc Sanitari Sant Joan de Déu, Camí Vell de la Colònia, 25, 08830 Sant Boi de Llobregat, Barcelona, Spain. Alvaro Díaz, Servei de Pediatria i Recerca, Fundació Hospital de Nens de Barcelona, C/Consell de Cent, 437, 08009 Barcelona, Spain. Maria Teresa Martin, Servei de Microbiologia, Hospital Universitari Vall d’Hebron, Pg. De la Vall d’Hebron, 119–129, 08035 Barcelona, Spain. Jaume Llaberia, Laboratori de Microbiologia, SCIAS Hospital de Barcelona, C/Diagonal, 660, 08034 Barcelona, Spain. Margarida Curriu, Servei de Microbiologia, Hospital Sant Bernabé, Ctra. de Ribes, s/n, 08600 Berga, Spain. Carme Gallés, Unitat de Microbiologia, Servei d'Anàlisis Clíniques, Corporació de Salut del Maresme i la Selva, C/Sant Jaume, 209–217, 08370 Calella, Barcelona, Spain. Elisenda Capdevila, Unitat de Microbiologia, Servei d'Anàlisis Clíniques, Corporació de Salut del Maresme i la Selva, C/Sant Jaume, 209–217, 08370 Calella, Barcelona, Spain. Paula Gassiot, Àrea de Microbiologia, Laboratori d’Anàlisis Clíniques, Hospital de Figueres, Rda. Rector Arolas, s/n, 17600 Figueres, Girona, Spain. Matilde Martínez-Zurita, Àrea de Microbiologia, Laboratori Clínic - Institut Català de la Salut Girona, Hospital Universitari Dr. Josep Trueta, Av. França, s/n, 17007 Girona, Spain. Carmina Martí, Laboratori de Microbiologia, Hospital General de Granollers, Av. Francesc Ribas, s/n, 08402 Granollers, Barcelona, Spain. Montserrat Morta, Servei de Microbiologia, Hospital Sant Joan de Déu, Fundació ALTHAIA, C/Dr. Joan Soler, s/n, 08243 Manresa, Barcelona, Spain. Goretti Sauca, Servei d’Análisis Clíniques, Secció de Microbiologia, Hospital de Mataró, Ctra. de Cirera, 230, 08304 Mataró, Barcelona, Spain. Asunción Gassós, Servei de Microbiologia, Sant Joan de Déu de Martorell, Av. Mancomunitats Comarcals, 1–3, 08760 Martorell, Barcelona, Spain. Esther Sanfeliu, Servei d’Anàlisis Clíniques, Secció de Microbiologia, Hospital d’Olot Comarcal de la Garrotxa, Av. dels Països Catalans, 86, 17800 Olot, Girona, Spain. Frederic Ballester, Laboratori de Referencia Sud, Hospital Sant Joan de Reus, Av. Dr Josep Laporte, 2, 43204 Reus, Tarragona, Spain. Isabel Pujol, Laboratori de Referencia Sud, Hospital Sant Joan de Reus, Av. Dr Josep Laporte, 2, 43204 Reus, Tarragona, Spain. Montserrat Olsina, Laboratori d’Anàlisis Clínics, Microbiologia, Hospital General de Catalunya, C/Pedro i Pons, 1, 08190 Sant Cugat del Vallès, Barcelona, Spain. Xavier Raga, Laboratori de Microbiologia, Hospital Sant Pau i Santa Tecla, Rambla Vella, 14, 43003 Tarragona, Spain. Frederic Gómez-Bertomeu, Àrea de Microbiologia, Laboratori Clínic ICS - Camp de Tarragona, Hospital Joan XXIII, C/Dr. Mallafrè Guasch, 4, 43005 Tarragona, Spain. Mar Olga Pérez-Moreno, Àrea de Microbiologia, Laboratori Clínic ICS - Terres de l’Ebre, Hospital Verge de la Cinta, C/de les Esplanetes, 14, 43500 Tortosa, Tarragona, Spain. Anna Vilamala, Servei de Microbiologia, Consorci Hospitalari de Vic, C/Francesc Pla 'El Vigatà', 1, 08500 Vic, Barcelona, Spain. Maria Navarro, Servei de Microbiologia, Consorci Hospitalari de Vic, C/Francesc Pla ‘El Vigatà’, 1, 08500 Vic, Barcelona, Spain. Mercè Ribelles, Secció Microbiologia, Servei d'Anàlisis Clíniques, Hospital Universitari Arnau de Vilanova de Lleida, Av. Rovira Roure, 80, 25198 Lleida, Barcelona, Spain. Mercè Garcia, Secció Microbiologia, Servei d'Anàlisis Clíniques, Hospital Universitari Arnau de Vilanova de Lleida, Av. Rovira Roure, 80, 25198 Lleida, Barcelona, Spain. Eduardo Padilla, Laboratori de Referència Catalunya, C/de la Selva, 10, 08820 Prat de Llobregat (El), Barcelona, Spain. Nuria Prim, Laboratori de Referència Catalunya, C/de la Selva, 10, 08820 Prat de Llobregat (El), Barcelona, Spain. Dionisia Fontanals, Secció de Microbiologia, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, UAB, C/Parc del Taulí, 1, 08208 Sabadell, Barcelona, Spain. Isabel Sanfeliu, Secció de Microbiologia, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, UAB C/Parc del Taulí, 1, 08208 Sabadell, Barcelona, Spain. Miguel Angel Benítez, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n, 08720 Vilafranca del Penedès, Barcelona, Spain. Eulalia Jou, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n, 08720 Vilafranca del Penedès, Barcelona, Spain. Carmina Sanjosé, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n 08720 Vilafranca del Penedès, Barcelona, Spain. Montserrat Giménez, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Ctra. de Canyet, s/n 08916 Badalona, Barcelona, Spain. Maria Dolores Quesada, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Ctra. de Canyet, s/n 08916 Badalona, Barcelona, Spain. Jose Carlos de la Fuente, Servei de Microbiologia, Hospital Comarcal Móra d’Ebre, C/de Benet Messeguer, s/n 43770 Móra d'Ebre, Tarragona, Spain. Ana Calderon, Servei de Microbiologia, Hospital Municipal de Badalona, C/Via Augusta, 9–13, 08911 Badalona, Barcelona, Spain. Percy Juan Ayala, Servei de Microbiologia, Clínica Terres de l’Ebre, Pl. De Joaquim Bau, 6–8, 43500 Tortosa, Tarragona, Spain. Josefa Pérez-Jové, Departament de Microbiologia, Catlab - Centre Analítiques Terrassa, AIE, Parc Logístic de Salut, Vial Sant Jordi, s/n, 08232 Viladecavalls, Barcelona, Spain. Ana Blanco, Departament de Microbiologia, Catlab - Centre Analítiques Terrassa, AIE, Parc Logístic de Salut, Vial Sant Jordi, s/n 08232, Viladecavalls, Barcelona, Spain. Conchita Balado, Departament de Microbiologia Clínica, Laboratori d’Anàlisis Dr. F Echevarne, C/de los Castillejos, 365, 08025 Barcelona, Spain. Ines Valle, Departament de Microbiologia Clínica, Laboratori d’Anàlisis Dr. F Echevarne, C/de los Castillejos, 365, 08025 Barcelona, Spain. Maria Teresa Bastida, Laboratori de Microbiologia, Fundació Hospital Esperit Sant, C/Pons i Rabadà s/n, 08923 Santa Coloma de Gramenet, Spain. Olga Gonzalez-Moreno, Laboratori de Microbiologia, SYNLAB Diagnósticos Globales S.A.U., C/Verge de Guadalupe, 18, 08950 Esplugues de Llobregat, Spain. Amaia Oteiza Ubanell, Laboratori d’Anàlisis Clíniques, Hospital de Palamós, C/Hospital, 36, 17230 Palamós, Spain.
    Authors List
  • Author Footnotes
    1 The Catalan Working Group on Invasive Pneumococcal Disease: Cristina Esteva, Departament de Microbiologia Molecular, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Mariona Fernández de Sevilla, Servei de Pediatria, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Desiree Henares, Departament de Microbiologia Molecular, Hospital Universitari Sant Joan de Déu, Pg. Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Carmen Ardanuy, Hospital Universitari de Bellvitge, Universitat de Barcelona, C/Feixa Llarga s/n, 08907 L’Hospitalet, Barcelona, Spain. Francesc Marco, Servei de Microbiologia, Hospital Clínic de Barcelona, C/Villarroel, 170, 08036 Barcelona, Spain. Nuria Margall, Servei de Microbiologia, Hospital Santa Creu i Sant Pau, C/de Sant Quintí, 89, 08041 Barcelona, Spain. Araceli González-Cuevas, Laboratori de Microbiologia, Hospital General del Parc Sanitari Sant Joan de Déu, Camí Vell de la Colònia, 25, 08830 Sant Boi de Llobregat, Barcelona, Spain. Alvaro Díaz, Servei de Pediatria i Recerca, Fundació Hospital de Nens de Barcelona, C/Consell de Cent, 437, 08009 Barcelona, Spain. Maria Teresa Martin, Servei de Microbiologia, Hospital Universitari Vall d’Hebron, Pg. De la Vall d’Hebron, 119–129, 08035 Barcelona, Spain. Jaume Llaberia, Laboratori de Microbiologia, SCIAS Hospital de Barcelona, C/Diagonal, 660, 08034 Barcelona, Spain. Margarida Curriu, Servei de Microbiologia, Hospital Sant Bernabé, Ctra. de Ribes, s/n, 08600 Berga, Spain. Carme Gallés, Unitat de Microbiologia, Servei d'Anàlisis Clíniques, Corporació de Salut del Maresme i la Selva, C/Sant Jaume, 209–217, 08370 Calella, Barcelona, Spain. Elisenda Capdevila, Unitat de Microbiologia, Servei d'Anàlisis Clíniques, Corporació de Salut del Maresme i la Selva, C/Sant Jaume, 209–217, 08370 Calella, Barcelona, Spain. Paula Gassiot, Àrea de Microbiologia, Laboratori d’Anàlisis Clíniques, Hospital de Figueres, Rda. Rector Arolas, s/n, 17600 Figueres, Girona, Spain. Matilde Martínez-Zurita, Àrea de Microbiologia, Laboratori Clínic - Institut Català de la Salut Girona, Hospital Universitari Dr. Josep Trueta, Av. França, s/n, 17007 Girona, Spain. Carmina Martí, Laboratori de Microbiologia, Hospital General de Granollers, Av. Francesc Ribas, s/n, 08402 Granollers, Barcelona, Spain. Montserrat Morta, Servei de Microbiologia, Hospital Sant Joan de Déu, Fundació ALTHAIA, C/Dr. Joan Soler, s/n, 08243 Manresa, Barcelona, Spain. Goretti Sauca, Servei d’Análisis Clíniques, Secció de Microbiologia, Hospital de Mataró, Ctra. de Cirera, 230, 08304 Mataró, Barcelona, Spain. Asunción Gassós, Servei de Microbiologia, Sant Joan de Déu de Martorell, Av. Mancomunitats Comarcals, 1–3, 08760 Martorell, Barcelona, Spain. Esther Sanfeliu, Servei d’Anàlisis Clíniques, Secció de Microbiologia, Hospital d’Olot Comarcal de la Garrotxa, Av. dels Països Catalans, 86, 17800 Olot, Girona, Spain. Frederic Ballester, Laboratori de Referencia Sud, Hospital Sant Joan de Reus, Av. Dr Josep Laporte, 2, 43204 Reus, Tarragona, Spain. Isabel Pujol, Laboratori de Referencia Sud, Hospital Sant Joan de Reus, Av. Dr Josep Laporte, 2, 43204 Reus, Tarragona, Spain. Montserrat Olsina, Laboratori d’Anàlisis Clínics, Microbiologia, Hospital General de Catalunya, C/Pedro i Pons, 1, 08190 Sant Cugat del Vallès, Barcelona, Spain. Xavier Raga, Laboratori de Microbiologia, Hospital Sant Pau i Santa Tecla, Rambla Vella, 14, 43003 Tarragona, Spain. Frederic Gómez-Bertomeu, Àrea de Microbiologia, Laboratori Clínic ICS - Camp de Tarragona, Hospital Joan XXIII, C/Dr. Mallafrè Guasch, 4, 43005 Tarragona, Spain. Mar Olga Pérez-Moreno, Àrea de Microbiologia, Laboratori Clínic ICS - Terres de l’Ebre, Hospital Verge de la Cinta, C/de les Esplanetes, 14, 43500 Tortosa, Tarragona, Spain. Anna Vilamala, Servei de Microbiologia, Consorci Hospitalari de Vic, C/Francesc Pla 'El Vigatà', 1, 08500 Vic, Barcelona, Spain. Maria Navarro, Servei de Microbiologia, Consorci Hospitalari de Vic, C/Francesc Pla ‘El Vigatà’, 1, 08500 Vic, Barcelona, Spain. Mercè Ribelles, Secció Microbiologia, Servei d'Anàlisis Clíniques, Hospital Universitari Arnau de Vilanova de Lleida, Av. Rovira Roure, 80, 25198 Lleida, Barcelona, Spain. Mercè Garcia, Secció Microbiologia, Servei d'Anàlisis Clíniques, Hospital Universitari Arnau de Vilanova de Lleida, Av. Rovira Roure, 80, 25198 Lleida, Barcelona, Spain. Eduardo Padilla, Laboratori de Referència Catalunya, C/de la Selva, 10, 08820 Prat de Llobregat (El), Barcelona, Spain. Nuria Prim, Laboratori de Referència Catalunya, C/de la Selva, 10, 08820 Prat de Llobregat (El), Barcelona, Spain. Dionisia Fontanals, Secció de Microbiologia, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, UAB, C/Parc del Taulí, 1, 08208 Sabadell, Barcelona, Spain. Isabel Sanfeliu, Secció de Microbiologia, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, UAB C/Parc del Taulí, 1, 08208 Sabadell, Barcelona, Spain. Miguel Angel Benítez, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n, 08720 Vilafranca del Penedès, Barcelona, Spain. Eulalia Jou, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n, 08720 Vilafranca del Penedès, Barcelona, Spain. Carmina Sanjosé, Servei de Microbiologia, CLILAB Diagnòstics, C/Espirall, s/n 08720 Vilafranca del Penedès, Barcelona, Spain. Montserrat Giménez, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Ctra. de Canyet, s/n 08916 Badalona, Barcelona, Spain. Maria Dolores Quesada, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Ctra. de Canyet, s/n 08916 Badalona, Barcelona, Spain. Jose Carlos de la Fuente, Servei de Microbiologia, Hospital Comarcal Móra d’Ebre, C/de Benet Messeguer, s/n 43770 Móra d'Ebre, Tarragona, Spain. Ana Calderon, Servei de Microbiologia, Hospital Municipal de Badalona, C/Via Augusta, 9–13, 08911 Badalona, Barcelona, Spain. Percy Juan Ayala, Servei de Microbiologia, Clínica Terres de l’Ebre, Pl. De Joaquim Bau, 6–8, 43500 Tortosa, Tarragona, Spain. Josefa Pérez-Jové, Departament de Microbiologia, Catlab - Centre Analítiques Terrassa, AIE, Parc Logístic de Salut, Vial Sant Jordi, s/n, 08232 Viladecavalls, Barcelona, Spain. Ana Blanco, Departament de Microbiologia, Catlab - Centre Analítiques Terrassa, AIE, Parc Logístic de Salut, Vial Sant Jordi, s/n 08232, Viladecavalls, Barcelona, Spain. Conchita Balado, Departament de Microbiologia Clínica, Laboratori d’Anàlisis Dr. F Echevarne, C/de los Castillejos, 365, 08025 Barcelona, Spain. Ines Valle, Departament de Microbiologia Clínica, Laboratori d’Anàlisis Dr. F Echevarne, C/de los Castillejos, 365, 08025 Barcelona, Spain. Maria Teresa Bastida, Laboratori de Microbiologia, Fundació Hospital Esperit Sant, C/Pons i Rabadà s/n, 08923 Santa Coloma de Gramenet, Spain. Olga Gonzalez-Moreno, Laboratori de Microbiologia, SYNLAB Diagnósticos Globales S.A.U., C/Verge de Guadalupe, 18, 08950 Esplugues de Llobregat, Spain. Amaia Oteiza Ubanell, Laboratori d’Anàlisis Clíniques, Hospital de Palamós, C/Hospital, 36, 17230 Palamós, Spain.
Open AccessPublished:July 05, 2019DOI:https://doi.org/10.1016/j.ijid.2019.06.030

      Highlights

      • Overall invasive pneumococcal disease (IPD) decreased by 19% in older adults due to the impact of childhood 13-valent pneumococcal conjugate vaccine (PCV13) vaccination.
      • IPD caused by non-PCV13 serotypes increased by 36% in older adults.
      • During 2014–2016, the IPD mortality rate was 17.5%.
      • The IPD mortality risk was found to be associated with older age, clinical form, high-risk conditions, and PCV13 serotypes.
      • Improving PCV13 vaccination coverage in children and 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults will decrease the incidence and severity of IPD in older adults.

      Abstract

      Objectives

      The aim of this study was to assess the indirect effect of paediatric 13-valent pneumococcal conjugate vaccine (PCV13) vaccination on people ≥65 years of age with invasive pneumococcal disease (IPD) in Catalonia and to determine factors predictive of mortality.

      Methods

      During 2014–2016, 1285 IPD cases were reported to the Public Health Agency of Catalonia. The indirect effect of paediatric PCV13 vaccination was calculated by comparing the incidence rate (IR) in 2016 (PCV13 year) with that in 2009 (pre-PCV13). Predictors of mortality were determined using multivariate logistic regression.

      Results

      Comparing 2016 and 2009, IPD decreased by 19% (IR 40.1 and 32.5 per 100 000 person-years, respectively). PCV13 serotypes decreased by 57% (IR 23.7 and 10.1), while non-PCV13 serotypes increased by 36% (IR 16.4 and 22.4). During 2014–2016, the mortality rate was 17.5%, and mortality was associated with age ≥85 years (adjusted odds ratio (aOR) 2.91, 95% confidence interval (CI) 1.89, 4.48), meningitis (aOR 2.29, 95% CI 1.25, 4.19), non-focal bacteraemia (aOR 3.73, 95% CI 2.00, 6.94), and ≥1 high-risk condition (aOR 1.89, 95% CI 1.08, 3.32). PPV23non13 serotypes were associated with lower mortality than PCV13 serotypes (aOR 0.54, 95% CI 0.34, 0.86).

      Conclusions

      The incidence of IPD in people ≥65 years of age decreased after the introduction of paediatric PCV13, and this was due to a reduction in PCV13 serotypes, although an increase in non-PCV13 serotypes was observed. Mortality was associated with age, meningitis, non-focal bacteraemia, ≥1 high-risk condition, and PCV13 serotypes.

      Keywords

      Introduction

      Streptococcus pneumoniae is a leading cause of severe disease worldwide, causing around one million deaths annually that affect mainly children and older people (
      • Liu L.
      • Oza S.
      • Hogan D.
      • Chu Y.
      • Perin J.
      • Zhu J.
      • et al.
      Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the sustainable development goals.
      ). Immunization of children with pneumococcal conjugate vaccines (PCV) has reduced the incidence of invasive pneumococcal disease (IPD) due to PCV serotypes in children, as well as in unvaccinated age groups, due to herd protection. However, other non-vaccine serotypes have emerged in children and adults (
      • Whitney C.G.
      • Farley M.M.
      • Hadler J.
      • Harrison L.H.
      • Bennett N.M.
      • Lynfield R.
      • et al.
      Decline in invasive pneumococcal disease after the introduction of protein–polysaccharide conjugate vaccine.
      ,
      • Pilishvili T.
      • Lexau C.
      • Farley M.M.
      • Hadler J.
      • Harrison L.H.
      • Bennett N.M.
      • et al.
      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ,
      • Pelton S.I.
      • Loughlin A.M.
      • Marchant C.D.
      Seven valent pneumococcal conjugate vaccine immunization in two Boston communities: changes in serotypes and antimicrobial susceptibility among Streptococcus pneumoniae isolates.
      ).
      The 23-valent pneumococcal polysaccharide vaccine (PPV23) has been indicated for people aged ≥65 years and those aged <65 years at increased risk of IPD (
      • Pebody R.G.
      • Leino T.
      • Nohynek H.
      • Hellenbrand W.
      • Salmaso S.
      • Ruutu P.
      Pneumococcal vaccination policy in Europe.
      ) since 1983. In 2012, the Advisory Committee on Immunization Practices recommended one dose of PCV13 vaccine followed by one dose of PPV23 at least 8 weeks later in people aged ≥19 years with high-risk conditions (
      • Centers for Disease Control and Prevention (CDC)
      Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ).
      In Catalonia, Spain, PPV23 was introduced for persons aged >2 years with a high-risk condition and older adults in 1999 (
      • Generalitat de Catalunya
      Prevenció de la malaltia pneumocòccica en els adults i en els infants a partir dels 5 anys a Catalunya. Programa de vacunacions.
      ). The 13-valent pneumococcal conjugate vaccine (PCV13) was included in the routine vaccination schedule for children in 2016 and recommended for persons with high-risk conditions. Prior to this date, children aged <5 years with risk factors were vaccinated with PCV13 free of charge, and in addition, other children were vaccinated with available PCVs according to the recommendation of their paediatrician ().
      Factors related to the host, such as age and underlying diseases (
      • Hausdorff W.P.
      • Bryant J.
      • Paradiso P.R.
      • Siber G.R.
      Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I.
      ,
      • Feikin D.R.
      • Schuchat A.
      • Kolczak M.
      • Barrett N.L.
      • Harrison L.H.
      • Lefkowitz L.
      • et al.
      Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997.
      ,
      • Niederman M.S.
      • Mandell L.A.
      • Anzueto A.
      • Bass J.B.
      • Broughton W.A.
      • Campbell G.D.
      • et al.
      Guidelines for the management of adults with community-acquired pneumonia.
      ,
      • Moroney J.F.
      • Fiore A.E.
      • Harrison L.H.
      • Patterson J.E.
      • Farley M.M.
      • Jorgensen J.H.
      • et al.
      Clinical outcomes of bacteremic pneumococcal pneumonia in the era of antibiotic resistance.
      ,
      • Yu V.L.
      • Chiou C.C.
      • Feldman C.
      • Ortqvist A.
      • Rello J.
      • Morris A.J.
      • et al.
      An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome.
      ), and factors related to the bacteria (serotype) (
      • Gilbert K.
      • Fine M.J.
      Assessing prognosis and predicting patient outcomes in community-acquired pneumonia.
      ,
      • Henriques B.
      • Kalin M.
      • Örtqvist Å.
      • Olsson Liljequist B.
      • Almela M.
      • Marrie T.J.
      • et al.
      Molecular epidemiology of Streptococcus pneumoniae causing invasive disease in 5 countries.
      ) have been associated with an increased susceptibility to IPD and greater mortality in adults.
      The objectives of this study were to assess the indirect effect of PCV13 vaccination in children on people ≥65 years of age in Catalonia and to determine the factors predictive of the IPD case fatality rate in this age group.

      Methods

      Study population

      The Catalan population ≥65 years of age was 1,217,519 in 2009 and increased to 1,379,277 by 2016 (

      Institut d’Estadística de Catalunya. https://www.idescat.cat/. [Accessed 18 January 2019].

      ).

      Case definition

      An IPD case was defined as a patient aged ≥65 years with clinical symptoms of infection (e.g., pneumonia, meningitis) together with S. pneumoniae isolation by culture or S. pneumoniae DNA detection by PCR or antigen detection in a normally sterile site (e.g., blood, cerebrospinal fluid, pleural fluid, joint fluid, peritoneal fluid, or lung tissue). Only one IPD episode per patient was included, unless clinical sample collection dates were separated by >30 days or the serotypes identified differed.

      Vaccination policy and vaccine uptake

      The estimated 7-valent PCV (PCV7) coverage in Catalonia was 58.7% in children aged <5 years (2007–2009) (
      • Ciruela P.
      • Soldevila N.
      • Hernández S.
      • Selva L.
      • de Sevilla M.F.
      • García-García J.J.
      • et al.
      Risk factors for invasive pneumococcal disease in a community with a high proportion of non vaccine serotypes.
      ). PCV13 and 10-valent PCV coverage in children aged <2 years was 64% and 4%, respectively (2012–2013) (
      • Savulescu C.
      • Krizova P.
      • Lepoutre A.
      • Mereckiene J.
      • Vestrheim D.F.
      • Ciruela P.
      • et al.
      Effect of high-valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children in SpIDnet countries: an observational multicentre study.
      ). Estimated PPV23 coverage was around 50% in older people in 2005–2007 (
      • Dominguez A.
      • Izquierdo C.
      • Salleras L.
      • Ruiz L.
      • Sousa D.
      • Bayas J.-M.
      • et al.
      Effectiveness of the pneumococcal polysaccharide vaccine in preventing pneumonia in the elderly.
      ).

      Surveillance system

      An active and retrospective study of all laboratory-confirmed IPD cases reported to the Microbiological Reporting System (MRS) of the Public Health Agency of Catalonia was conducted. The MRS involves 50 centres, representing over 85% of hospital beds in public hospitals. All Catalonian reference hospitals were included. In addition, cases from some private hospitals that send strains to regional and national reference laboratories were also recovered in order to study the serotypes (
      • Ciruela P.
      • Izquierdo C.
      • Broner S.
      • Muñoz-Almagro C.
      • Hernández S.
      • Ardanuy C.
      • et al.
      The changing epidemiology of invasive pneumococcal disease after PCV13 vaccination in a country with intermediate vaccination coverage.
      ).
      The variables included were age, sex, clinical form, serotype and antibiotic susceptibility. Clinical form was stratified into pneumonia, empyema, non-focal bacteraemia, meningitis, and other clinical forms. Serotyping and antibiotic susceptibility testing were performed by the Public Health Support Laboratory of Catalonia (Sant Joan de Déu University Hospital) and the National Centre for Microbiology – Instituto de Salud Carlos III (Madrid, Spain) as described previously (
      • Fenoll A.
      • Jado I.
      • Vicioso D.
      • Casal J.
      Dot blot assay for the serotyping of pneumococci.
      ). Meningeal breakpoints for penicillin were considered for the epidemiological analysis (
      • The European Committee on Antimicrobial Susceptibility Testing
      Breakpoint tables for interpretation of MICs and zone diameters.
      ). Isolates with intermediate or high-level resistance were defined as non-susceptible.
      The date of hospitalization, intensive care unit (ICU) admission, IPD-predisposing comorbidities, vaccination history (PPV23, influenza vaccine in the current season), and mortality (30-day mortality) were collected from the medical records. Comorbidities were divided into two mutually-exclusive categories: (1) high risk, including chronic renal failure, HIV, immunodeficiency (medically induced or innate), asplenia, haematological or metastatic malignancies, CSF leak, and prior neurosurgery, and (2) at risk, including diabetes mellitus, congestive heart failure, chronic lung disease, cirrhosis, smoking, and alcoholism (
      • Centers for Disease Control and Prevention (CDC)
      Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ). The presence of ≥2 comorbidities was classified as ‘>1 high-risk condition’, if one of them was a high-risk condition, and as ‘>1 at-risk condition’ otherwise.
      The length of hospital stay was classified as <15 days or ≥15 days. The time since the last PPV23 dose was classified as <5 years or ≥5 years. Cases were considered vaccinated with PPV23 or influenza vaccine when they had received a dose of either vaccine at least 14 days before symptom onset.

      Data analysis

      The data analysis was performed by comparison of the year 2009 data (baseline year prior to marketing of PCV13) to the year 2016 data, when PCV13 was included in the paediatric vaccination schedule. Some data from 2014, 2015, and 2016 were also included when performing the analysis of pneumococcal serotypes, in order to increase the sample size. The variables studied were the number of cases, incidence rates (IR), sex, age group, clinical form, serotype categories, and antibiotic susceptibility. The age groups considered were 65–74 years, 75–84 years, and ≥85 years. Serotypes were grouped into four categories by vaccine coverage: PCV7 (included serotypes: 4, 6B, 9V, 14, 18C, 19F, and 23F), PCV13non7 (included serotypes: 1, 3, 5, 6A, 7F, and 19A), PPV23non13 (included serotypes: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F), and nonPPV23 serotypes (serotypes not included in PPV23 and not serotype 6A).
      The indirect effect of PCV13 in people ≥65 years of age was calculated by comparing the IR in 2016 with the IR in 2009 by serotype category and age group. For cases with missing serotype information, it was assumed that the serotype distribution was the same as among cases with the known serotype in the same year and age group. Changes in the estimated IR were assessed by incidence rate ratios (IRR) with 95% confidence intervals (CI) and were expressed as the percentage change in incidence. Proportions were compared using the Chi-square test or Fisher’s exact test, as appropriate.
      To determine predictors of the case fatality rate during 2014–2016, multivariate logistic regression was used. The model included all variables with a value of p < 0.2 in the univariate regression analyses. The odds ratios (OR) and 95% CI were calculated.
      Two-sided p-values of <0.05 were considered statistically significant. The analyses were conducted using the IBM SPSS Statistics version 19.0 (IBM Corp., Armonk, NY, USA) and R 2.13.0 (R Development Core Team 2014).

      Results

      Characteristics of IPD in people older than 64 years of age

      A total of 488 IPD cases were reported in 2009 compared to 448 cases in 2016 (Table 1). The highest number of cases was in the 75–84 years age group in 2009 (41.4%) and in the 65–74 years age group in 2016 (37.5%). There was an increase in cases in the ≥85 years age group (24.2% vs. 30.4%; p =  0.039) and a decrease in the 75–84 years age group (41.4% vs. 32.1%; p =  0.004) in 2016 compared to 2009. The predominant clinical form was pneumonia (83.8% in 2009, 82.4% in 2016). More than a quarter of patients were admitted to the ICU in 2009 (25.4%) and 21.2% in 2016. There was no change between 2009 and 2016 regarding clinical forms, hospitalization, and ICU admission.
      Table 1Changes in demographic, clinical, and microbiological characteristics of patients ≥65 years of age with IPD before and after the introduction of PCV13; Catalonia, 2009 and 2016.
      2009 (n = 488)2016 (n = 448)p-Value
      n (%)n (%)
      Age group (years)
       65–74168 (34.4)168 (37.5)0.340
       75–84202 (41.4)144 (32.1)0.004
       ≥85118 (24.2)136 (30.4)0.039
      Sex
       Male264 (54.1)252 (56.3)0.512
      Clinical presentation
       All pneumonia409 (83.8)369 (82.4)0.600
      Empyema30 (6.1)18 (4.0)0.181
       Non-focal bacteraemia37 (7.6)28 (6.3)0.443
       Meningitis26 (5.3)38 (8.5)0.069
       Other forms
      Other forms: abdominal (15 cases), osteoarticular (10 cases), cellulitis (3 cases), endocarditis (1 case).
      16 (3.3)13 (2.9)0.851
      Hospitalization
      (
      2009.
      n = 357;
      2016.
      n = 428)
       Yes350 (98.0)416 (97.2)0.492
      Length of hospital stay
      (
      2009.
      n = 331;
      2016.
      n = 410)
       ≥15 days85 (25.6)287 (24.4)0.189
      ICU admission
      (
      2009.
      n = 225;
      2016.
      n = 414)
       Yes84 (25.4)87 (21.2)1
      Underlying diseases
      (
      2009.
      n = 302;
      2016.
      n = 414)
       At risk157 (52)213 (49.6)0.548
      Chronic cardiovascular disease58 (19.2)57 (13.3)0.039
      Chronic lung disease12 (4.0)18 (4.2)1
      Diabetes19 (6.3)34 (7.9)0.470
      Cirrhosis4 (1.3)5 (1.2)1
      Alcoholism1 (0.3)1 (0.2)1
      Smoking3 (1.0)1 (0.2)0.388
      CSF leakage0 (0.0)2 (0.5)0.639
      >1 at-risk condition60 (19.9)95 (22.1)0.520
       High risk102 (33.8)159 (37)0.389
      Chronic renal disease4 (1.3)19 (4.4)0.018
      Immunodeficiency34 (11.3)25 (5.8)0.009
      Asplenia0 (0.0)0 (0.0)1
      Transplant1 (0.3)0 (0.0)0.860
      >1 high-risk condition63 (20.9)115 (26.8)0.067
       No condition43 (14.2)57 (13.3)0.744
      Influenza vaccination
      (
      2009.
      n = 445;
      2016.
      n = 439)
       Yes199 (44.7)202 (46.0)0.736
      PPV23 vaccination
       Vaccinated184 (41.3)270 (61.5)<0.001
      (
      2009.
      n = 445;
      2016.
      n = 439)
      PPV23 ≥ 5 years112 (60.9)216 (80.0)<0.001
      PPV23 < 5 years72 (39.1)54 (20.0)<0.001
       Non-vaccinated261 (58.7)169 (38.5)<0.001
      Penicillin
      (
      2009.
      n = 420;
      2016.
      n = 372)
       Non-susceptible104 (24.8)97 (26.1)0.683
      Cefotaxime
      (
      2009.
      n = 420;
      2016.
      n = 372)
       Non-susceptible47 (11.2)51 (13.7)0.334
      Abbreviations: IPD, invasive pneumococcal disease; PCV13, 13-valent pneumococcal conjugate vaccine; CSF leakage, cerebral spinal fluid leakage; ICU, intensive care unit; PPV23, 23-valent pneumococcal polysaccharide vaccine.
      a Other forms: abdominal (15 cases), osteoarticular (10 cases), cellulitis (3 cases), endocarditis (1 case).
      * 2009.
      ** 2016.
      One hundred and fifty-seven cases (52.0%) had ≥1 at-risk comorbidity in 2009 compared to 213 cases (49.6%) in 2016. Furthermore, 102 (33.8%) cases in 2009 compared to 159 (37.0%) cases in 2016 had ≥1 high-risk comorbidity. There were no significant differences between these categories in the years analysed. Only chronic cardiovascular disease (19.2% vs. 13.3%; p = 0.039) and immunodeficiency (11.3% vs. 5.8%; p = 0.009) declined in 2016, whereas chronic renal disease increased (1.3% vs. 4.4%; p = 0.018). IPD cases vaccinated with PPV23 increased in 2016 (41.3% vs. 61.5%; p < 0.001), although cases vaccinated within the previous 5 years declined (39.1% vs. 20.0%; p < 0.001).
      Antibiotic susceptibility testing was performed on 420 (86.1%) isolates in 2009 and 372 (83.0%) isolates in 2016; of these, 24.8% and 26.1% (p = 0.683), respectively, were non-susceptible to penicillin and 11.2% and 13.7% (p = 0.334), respectively, were non-susceptible to cefotaxime.

      Indirect effect of PCV13 on IPD in people older than 64 years of age

      During 2014–2016, the IPD IR was between 29.0 and 33.0 per 100 000 person-years in 2014 and 2015, respectively (Figure 1). The highest incidence was in the age group ≥85 years (52.0 in 2014 and 63.2 in 2016). The serotype was available in 1114 (86.7%) cases. The estimated serotypes included in PCV13, PPV23non13, and non-vaccine serotypes represented 34.8%, 35.0%, and 30.2% of cases, respectively. The most frequent serotypes were 3 (11.6%), 8 (8.3%), 14 (7.3%), 12F (6.8%), 22F (5.2%), and 19A (4.9%), which are included in PCV13 and PPV23 (Figure 2A, B).
      Figure 1
      Figure 1Estimated IPD incidence rate by year, age group and vaccine serotypes in patients aged ≥65 years. Catalonia, 2014–2016.
      Abbreviations: IPD, invasive pneumococcal disease; PCV7 serotypes, serotypes included in 7-valent pneumococcal conjugate vaccine; PCV13non7 serotypes, additional serotypes included in 13-valent pneumococcal conjugate vaccine; PPV23non13, additional serotypes included in 23-valent pneumococcal conjugate vaccine; Non-PPV23, serotypes not included in 23-valent pneumococcal polysaccharide vaccine and not 6A.
      Figure 2
      Figure 2(A) Estimated IPD incidence rate caused by PCV13 serotypes in patients aged ≥65 years. Catalonia, 2014–2016. (B) Estimated IPD incidence rate caused by PPV23non-PCV13 serotypes and non-PPV23 serotypes in patients aged ≥65 years. Catalonia, 2014–2016.
      Abbreviations: IPD, invasive pneumococcal disease; PCV7 serotypes, serotypes included in 7-valent pneumococcal conjugate vaccine; PCV13non7 serotypes, additional serotypes included in 13-valent pneumococcal conjugate vaccine; PPV23non13, additional serotypes included in 23-valent pneumococcal conjugate vaccine.
      Changes in estimated IR and serotype groups between 2009 and 2016 are shown in Table 2. Global IPD IR decreased by 19% in 2016 (40.1 and 32.5 per 100 000 person-years, respectively; IRR 0.81, 95% CI 0.71, 0.92). The incidence of serotypes included in PCV13 showed a decrease of 57% in 2016, mainly due to the PCV13non7 serotypes (70%). However, non-PCV13 serotypes increased by 36%, especially due to PPV23non13 serotypes (80%).
      Table 2Changes in estimated incidence rate of IPD by vaccine serotypes in patients ≥65 years of age before and after the introduction of PCV13 and estimates of the indirect effect; Catalonia, 2009 and 2016.
      Age and serotype categories20092016IRR (95% CI)Indirect effect estimates
      Note: A negative indirect effect indicates an increased incidence, while a positive effect indicates a decrease effect.
      % (95% CI)
      Estimated (raw) casesIREstimated (raw) casesIR
      ≥65 years48840.144832.50.81 (0.71, 0.92)19 (8, 29)
       PCV13288 (246)23.7139 (116)10.10.43 (0.35, 0.52)57 (48, 65)
        PCV779 (70)6.567 (56)4.90.75 (0.53, 1.05)25 (−5, 47)
        PCV13non7209 (176)17.272 (60)5.20.30 (0.23, 0.40)70 (60, 77)
       Non-PCV13200 (178)16.4309 (257)22.41.36 (1.14, 1.64)−36 (−64, −14)
        PPV23non1387 (78)7.1177 (145)12.81.8 (1.38, 2.35)−80 (−135, −38)
        Non-PPV23113 (100)9.3132 (112)9.61.03 (0.80, 1.34)−3 (−34, 20)
      65–74 years16828.416824.30.86 (0.69, 1.07)14 (−7, 31)
       PCV13104 (92)17.647 (39)6.80.39 (0.27, 0.55)61 (45, 73)
        PCV733 (29)5.620 (16)2.90.52 (0.28, 0.93)48 (7, 72)
        PCV13non771 (63)12.027 (23)3.90.33 (0.20, 0.51)67 (49, 80)
       Non-PCV1364 (57)10.8121 (104)17.51.62 (1.19, 2.23)−62 (−123, −19)
        PPV23non1329 (25)4.984 (71)12.22.48 (1.61, 3.92)−148 (−292, −61)
        Non-PPV2335 (32)5.937 (33)5.40.91 (0.55, 1.48)9 (−48, 45)
      75–84 years20243.414430.70.71 (0.57, 0.88)29 (12, 43)
       PCV13118 (97)25.448 (39)10.20.4 (0.28, 0.57)60 (43, 72)
        PCV726 (23)5.621 (17)4.50.80 (0.43, 1.48)20 (−42, 55)
        PCV13non792 (74)19.827 (22)5.80.29 (0.18, 0.45)71 (55, 81)
       Non-PCV1384 (72)18.196 (73)20.51.13 (0.84, 1.54)−13 (−54, 16)
        PPV23non1338 (33)8.251 (38)10.91.33 (0.86, 2.08)−33 (−108, 14)
        Non-PPV2346 (39)9.945 (35)9.60.97 (0.63, 1.50)3 (−50, 37)
      ≥85 years1187313661.60.84 (0.65, 1.09)16 (−9, 35)
       PCV1366 (57)40.844 (38)19.90.49 (0.33, 0.73)51 (27, 67)
        PCV720 (18)12.426 (23)11.80.95 (0.51, 1.80)5 (−80, 49)
        PCV13non746 (39)28.518 (15)8.20.29 (0.16, 0.50)71 (50, 84)
       Non-PCV1352 (49)32.292 (80)41.71.30 (0.91, 1.86)−30 (−86, 9)
        PPV23non1320 (20)12.442 (36)19.01.54 (0.88, 2.77)−54 (−177, 12)
        Non-PPV2332 (29)19.850 (44)22.71.14 (0.72, 1.84)−14 (−84, 28)
      Abbreviations: IPD, invasive pneumococcal disease; IR, incidence rate; IRR, incidence rate ratio; CI, confidence interval; PCV13, serotypes included in the 13-valent pneumococcal conjugate vaccine; PCV7, serotypes included in the 7-valent pneumococcal conjugate vaccine; PCV13non7, additional serotypes included in the 13-valent pneumococcal conjugate vaccine; Non-PCV13, serotypes not included in the 13-valent pneumococcal conjugate vaccine; PPV23non13, additional serotypes included in the 23-valent pneumococcal conjugate vaccine; Non-PPV23, serotypes not included in the 23-valent pneumococcal polysaccharide vaccine and not 6A.
      a Note: A negative indirect effect indicates an increased incidence, while a positive effect indicates a decrease effect.
      PCV13 serotypes decreased in all age groups, between 51% in people aged ≥85 years and 60% in those aged 75–84 years. Non-PCV13 serotypes increased in all age groups, but the difference was statistically significant only in the 65–74 years age group, increasing by 62% (10.8 and 17.5 per 100 000 person-years in 2009 and 2016, respectively; IRR 1.62, 95% CI 1.19, 2.23).

      Predictors of the case fatality rate

      During 2014–2016, there were 219/1253 fatal cases (17.5%), which increased with age from 12.2% in people aged 65–74 years to 25.7% in those aged ≥85 years (Table 3). The case fatality rate was higher in people with comorbidities (at-risk 15.6% and high-risk 21.2%) than in healthy people (13.9%). In the univariate analysis, older age, high-risk conditions, and clinical forms such as meningitis, non-focal bacteraemia, and other clinical forms were associated with greater mortality. IPD due to PPV23non13 serotypes had a lower case fatality rate than PCV13 serotypes, whereas non-susceptibility to penicillin and cefotaxime were risk factors for mortality.
      Table 3Predictors of death in IPD patients ≥65 years of age; Catalonia, 2014–2016.
      Death
      Yes (n = 219)No (n = 1,034)
      n (%)n (%)OR (95% CI)p-ValueaOR
      The model included all variables with a value of p < 0.20 in the univariate regression analysis.
      (95% CI)
      p-Value
      Age group (years)65-74 (n=467)57 (12.2)410 (87.8)11
      75-84 (n=440)73 (16.6)367 (83.4)1.43 (0.98,2.08)0.0601.50 (0.97,2.32)0.068
      ≥85 (n=346)89 (25.7)257 (74.3)2.49 (1.73,3.60)<0.0012.91 (1.89,4.48)<0.001
      SexFemale (n=556)103 (18.5)453 (81.5)1
      Male (n=697)116 (16.6)581 (83.4)1.14 (0.85,1.53)0.384
      Clinical presentationAll pneumonia (n=1,031)156 (15.1)875 (84.9)11
      Meningitis (n=99)24 (24.2)75 (75.8)1.80 (1.10,2.93)0.0192.29 (1.25,4.19)0.007
      Non-focal bacteraemia (n=68)24 (35.3)44 (64.7)3.06 (1.81,5.18)<0.0013.73 (2.00,6.94)<0.001
      Other forms (n=55)15 (27.3)40 (72.7)2.00 (1.13,3.90)0.0181.60 (0.76,3.41)0.219
      ComorbiditiesNo risk condition (n=180)25 (13.9)155 (86.1)11
      ≥1 at-risk condition (n=584)91 (15.6)493 (84.4)1.14 (0.71,1.85)0.5801.21 (0.69,2.10)0.508
      ≥1 high-risk condition (n=468)99 (21.2)369 (78.8)1.66 (1.03,2.68)0.0371.89 (1.08,3.32)0.027
      Serotypes categoriesPCV13 (n=378)76 (20.1)302 (79.9)11
      PPV23non13 (n=367)38 (10.4)329 (89.6)0.46 (0.30,0.70)<0.0010.54 (0.34,0.86)0.010
      Non-PPV23 (n=332)71 (21.4)261 (78.6)1.08 (0.75,1.56)0.6751.07 (0.69,1.65)0.768
      PenicillinSusceptible (n=778)120 (15.4)658 (84.6)11
      Non-susceptible (n=284)61
      Nine strains were resistant.
      (21.5)
      223
      Thirty-one strains were resistant.
      (78.5)
      1.50 (1.06,2.12)0.0210.91 (0.56,1.48)0.907
      CefotaximeSusceptible (n=935)151 (16.1)784 (83.9)11
      Non-susceptible (n=127)30
      One strain was resistant.
      (23.6)
      97
      Two strains were resistant.
      (76.4)
      1.61 (1.03,2.51)0.0371.38 (0.70,2.69)0.350
      Influenza vaccinationNot vaccinated (n=652)114 (17.5)538 (82.5)1
      Vaccinated (n=600)104 (17.3)496 (82.7)0.99 (0.74,1.33)0.944
      Abbreviations: IPD, invasive pneumococcal disease; OR, odds ratio; CI, confidence interval; aOR, adjusted odds ratio; PCV13, serotypes included in the 13-valent pneumococcal conjugate vaccine; PPV23non13, additional serotypes included in the 23-valent pneumococcal conjugate vaccine; Non-PPV23, serotypes not included in the 23-valent pneumococcal polysaccharide vaccine and not 6A.
      * The model included all variables with a value of p < 0.20 in the univariate regression analysis.
      a Nine strains were resistant.
      b Thirty-one strains were resistant.
      c One strain was resistant.
      d Two strains were resistant.
      Age, clinical form, high-risk condition, serotype by vaccine type, and antibiotic susceptibility to penicillin and cefotaxime had a p-value of <0.2 in the univariate analysis and were included in the final regression model. The case fatality rate showed a significant difference in people aged ≥85 years compared to those aged 65–74 years (adjusted OR 2.91, 95% CI 1.89, 4.48). Meningitis (adjusted OR 2.29, 95% CI 1.25, 4.19) and non-focal bacteraemia (adjusted OR 3.73, 95% CI 2.00, 6.94) remained associated with mortality. High-risk comorbidities were also associated with mortality (adjusted OR 1.89, 95% CI 1.08, 3.32). PPV23non13 serotypes were associated with lower mortality compared with PCV13 serotypes (adjusted OR 0.54, 95% CI 0.34, 0.86).
      Of the 219 deaths, 186 (84.9%) were serotyped, and the most frequent serotypes were 3 (17.2%), 14 (9.7%), 6C (6.5%), and 24 F (5.4%) (Figure 3). Of 1034 survivors, 899 were serotyped (86.9%), and the most frequent serotypes were 3 (10.5%), 14 (6.8%), and 6C (3.6%). Significant differences between those who died and those who survived were found for serotypes 3 (17.2% vs. 10.5%; p <  0.05), 8 (3.2% vs. 9.5%; p <  0.05), and 12F (1.6% vs. 7.8%; p <  0.05). In the 126 cases with serotype 3, there were 32 deaths (25.4%).
      Figure 3
      Figure 3Burden of mortality by serotype distribution in patients aged ≥65 years. Catalonia, 2014–2016.
      Abbreviations: ST, serotype.

      Discussion

      The incidence of IPD decreased slightly in people ≥65 years of age after the introduction of PCV13 in children. There was a decrease in PCV13 serotypes, but an important increase in non-PCV13 serotypes, especially in PPV23non13 serotypes.
      Other countries have reported IPD reduction rates ranging from 16% (
      • Regev-Yochay G.
      • Katzir M.
      • Strahilevitz J.
      • Rahav G.
      • Finn T.
      • Miron D.
      • et al.
      The herd effects of infant PCV7/PCV13 sequential implementation on adult invasive pneumococcal disease, six years post implementation; a nationwide study in Israel.
      ) to 42% (
      • Cabaj J.L.
      • Nettel-Aguirre A.
      • MacDonald J.
      • Vanderkooi O.G.
      • Kellner J.D.
      Influence of childhood pneumococcal conjugate vaccines on invasive pneumococcal disease in adults with underlying comorbidities in Calgary, Alberta (2000-2013).
      ,
      • Chalmers J.D.
      • Campling J.
      • Dicker A.
      • Woodhead M.
      • Madhava H.
      A systematic review of the burden of vaccine preventable pneumococcal disease in UK adults.
      ), and a greater decrease (65%) in PCV13 serotypes (
      • Regev-Yochay G.
      • Katzir M.
      • Strahilevitz J.
      • Rahav G.
      • Finn T.
      • Miron D.
      • et al.
      The herd effects of infant PCV7/PCV13 sequential implementation on adult invasive pneumococcal disease, six years post implementation; a nationwide study in Israel.
      ) than those found in the present study. A multicentre European study reported a lower decline in IPD incidence (9%) than in the present study, with large reductions in PCV13 serotypes and an increase in non-PCV13 serotypes (63%) in 2011–2015 compared with 2009 (
      • Hanquet G.
      • Krizova P.
      • Valentiner-Branth P.
      • Ladhani S.N.
      • Nuorti J.P.
      • Lepoutre A.
      • et al.
      Effect of childhood pneumococcal conjugate vaccination on invasive disease in older adults of 10 European countries: implications for adult vaccination.
      ).
      In the present study, the most frequent serotype in adults was serotype 3. This serotype represented one of the most frequent serotypes in other age groups since PCV13 was marketed in Catalonia (
      • Ciruela P.
      • Izquierdo C.
      • Broner S.
      • Muñoz-Almagro C.
      • Hernández S.
      • Ardanuy C.
      • et al.
      The changing epidemiology of invasive pneumococcal disease after PCV13 vaccination in a country with intermediate vaccination coverage.
      ). The lack of PCV13 effectiveness against serotype 3 in children may be the main reason why there was no reduction in its incidence (
      • Domínguez Á.
      • Ciruela P.
      • Hernández S.
      • García-García J.J.
      • Soldevila N.
      • Izquierdo C.
      • et al.
      Effectiveness of the 13-valent pneumococcal conjugate vaccine in preventing invasive pneumococcal disease in children aged 7-59 months. A matched case-control study.
      ). Other serotypes with high incidences were 8, 14, 12 F, and 22 F (all PPV23 serotypes, except for serotype 14, which is also included in PCV13).
      No differences were found in clinical form, ICU admission, and most of the comorbidities between 2009 and 2016, although cases with chronic cardiovascular disease and immunodeficiency decreased and cases with chronic renal disease increased. Sixty-one percent of IPD patients were vaccinated with PPV23, although the majority of them had been vaccinated ≥5 years before. It could be necessary to improve vaccination with PPV23 in older people, mainly those with risk factors for IPD. PPV23 effectiveness against IPD remains unclear (
      • Hanquet G.
      • Krizova P.
      • Valentiner-Branth P.
      • Ladhani S.N.
      • Nuorti J.P.
      • Lepoutre A.
      • et al.
      Effect of childhood pneumococcal conjugate vaccination on invasive disease in older adults of 10 European countries: implications for adult vaccination.
      ,
      • Marrie T.J.
      • Tyrrell G.J.
      • Garg S.
      • Vanderkooi O.G.
      Factors predicting mortality in invasive pneumococcal disease in adults in Alberta.
      ,
      • Jansen A.G.
      • Rodenburg G.D.
      • van der Ende A.
      • van Alphen L.
      • Veenhoven R.H.
      • Spanjaard L.
      • et al.
      Invasive pneumococcal disease among adults: associations among serotypes, disease characteristics, and outcome.
      ), but it is recommended in persons at risk of IPD and older people (). Studies on the effectiveness of PPV23 focusing on specific serotypes and the time of vaccination should be considered. The progressive decline in PCV13 serotypes and the gradual increase in PPV23non13 serotypes suggest that the potential benefits of PCV13 vaccination in adults should be regarded with caution.
      During 2014–2016, mortality due to IPD was 17.5%, which is lower than observed in other countries (24–30%) (
      • Harboe Z.B.
      • Thomsen R.W.
      • Riis A.
      • Valentiner-Branth P.
      • Christensen J.J.
      • Lambertsen L.
      • et al.
      Pneumococcal serotypes and mortality following invasive pneumococcal disease: a population-based cohort study.
      ,
      • Grau I.
      • Ardanuy C.
      • Cubero M.
      • Benitez M.A.
      • Liñares J.
      • Pallares R.
      Declining mortality from adult pneumococcal infections linked to children’s vaccination.
      ,
      • van Hoek A.J.
      • Andrews N.
      • Waight P.A.
      • George R.
      • Miller E.
      Effect of serotype on focus and mortality of invasive pneumococcal disease: coverage of different vaccines and insight into non-vaccine serotypes.
      ). The difference in mortality may be due, in part, to the characteristics of the population, the type of analysis, and differing serotype distributions.
      The study results showed that older age, meningitis or non-focal bacteraemia, high-risk conditions, and IPD caused by PCV13 serotypes were predictive factors of mortality after adjustment for possible confounding factors.
      Old age is an independent risk factor for mortality, as described in other studies (
      • Regev-Yochay G.
      • Katzir M.
      • Strahilevitz J.
      • Rahav G.
      • Finn T.
      • Miron D.
      • et al.
      The herd effects of infant PCV7/PCV13 sequential implementation on adult invasive pneumococcal disease, six years post implementation; a nationwide study in Israel.
      ,
      • Kim J.H.
      • Baik S.H.
      • Chun B.C.
      • Song J.Y.
      • Bae I.-G.
      • Kim H.Y.
      • et al.
      Adult invasive pneumococcal disease in the Republic of Korea: risk medical conditions and mortality stratified by age group.
      ,
      • Marrie T.J.
      • Tyrrell G.J.
      • Garg S.
      • Vanderkooi O.G.
      Factors predicting mortality in invasive pneumococcal disease in adults in Alberta.
      ). This is probably due to reduced immune function (
      • Jansen A.G.
      • Rodenburg G.D.
      • van der Ende A.
      • van Alphen L.
      • Veenhoven R.H.
      • Spanjaard L.
      • et al.
      Invasive pneumococcal disease among adults: associations among serotypes, disease characteristics, and outcome.
      ) and an increase in comorbidities (
      • Yu V.L.
      • Chiou C.C.
      • Feldman C.
      • Ortqvist A.
      • Rello J.
      • Morris A.J.
      • et al.
      An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome.
      ).
      The case fatality rate was higher in people with comorbidities than in healthy people, but only high-risk comorbidities were associated with mortality in the multivariate analysis. Other studies have reported an association between at-risk or high-risk conditions and mortality (
      • Regev-Yochay G.
      • Katzir M.
      • Strahilevitz J.
      • Rahav G.
      • Finn T.
      • Miron D.
      • et al.
      The herd effects of infant PCV7/PCV13 sequential implementation on adult invasive pneumococcal disease, six years post implementation; a nationwide study in Israel.
      ,
      • Grau I.
      • Ardanuy C.
      • Cubero M.
      • Benitez M.A.
      • Liñares J.
      • Pallares R.
      Declining mortality from adult pneumococcal infections linked to children’s vaccination.
      ), suggesting that the risk condition of the patient plays a decisive role in the outcome of IPD, and not only the biological characteristics of the microorganism, which is in agreement with the present study results. In contrast, other authors (
      • Kim J.H.
      • Baik S.H.
      • Chun B.C.
      • Song J.Y.
      • Bae I.-G.
      • Kim H.Y.
      • et al.
      Adult invasive pneumococcal disease in the Republic of Korea: risk medical conditions and mortality stratified by age group.
      ) have found no association with either chronic medical conditions or immunocompromised conditions after the introduction of PCV13 in children. The difference is probably due to the statistical analysis or the characteristics of the populations studied.
      The severity of clinical disease was associated with a high risk of mortality. Meningitis and non-focal bacteraemia were associated with mortality. Other authors (
      • Kim J.H.
      • Baik S.H.
      • Chun B.C.
      • Song J.Y.
      • Bae I.-G.
      • Kim H.Y.
      • et al.
      Adult invasive pneumococcal disease in the Republic of Korea: risk medical conditions and mortality stratified by age group.
      ) who included referral hospitals found an association with pneumonia, in contrast to our study. These differences may be explained by the fact that 85% of the reports in the present study corresponded to acute hospitals (including secondary and tertiary hospitals).
      PCV13 serotypes were independently associated with a higher case fatality rate compared with PPV23non13 serotypes. The most frequent serotypes causing disease in the patients who died were 3, 14, 6C, and 24F, but only serotype 3 was associated with greater mortality, in accordance with other studies (
      • Harboe Z.B.
      • Thomsen R.W.
      • Riis A.
      • Valentiner-Branth P.
      • Christensen J.J.
      • Lambertsen L.
      • et al.
      Pneumococcal serotypes and mortality following invasive pneumococcal disease: a population-based cohort study.
      ). Other authors (
      • van Hoek A.J.
      • Andrews N.
      • Waight P.A.
      • George R.
      • Miller E.
      Effect of serotype on focus and mortality of invasive pneumococcal disease: coverage of different vaccines and insight into non-vaccine serotypes.
      ) have found serotypes 19F, 31, and 3 to have the greatest mortality, with similar percentages (41%, 40%, and 39%, respectively). Serotype 3 has been associated with serious disease like empyema (
      • Ciruela P.
      • Soldevila N.
      • Selva L.
      • Hernández S.
      • Garcia-Garcia J.J.
      • Moraga F.
      • et al.
      Are risk factors associated with invasive pneumococcal disease according to different serotypes?.
      ), which could explain, in part, the association with mortality.
      This study has some limitations. First, there were some missing clinical data for 2009, the baseline year. However, the analysis of mortality predictors was performed using data from 2014–2016 with higher quality of information. Second, serotype information was missing in 14% of the cases; this limitation was addressed using estimates to calculate the indirect effect of PCV13 in adults.
      A strength of this study is the robust data recorded by the MRS, which included more than 85% of acute hospital beds. Another strength is that Catalonia has participated in the European multicentre SpIDnet project (https://sites.google.com/a/epiconcept.fr/ipd-surveillance/home-2) and this has substantially improved the IPD surveillance in our area.
      In summary, the incidence of IPD has decreased slightly in people aged ≥65 years due to the impact of childhood PCV13 vaccination although an increase of non-PCV13 serotypes was detected. The case fatality rate was associated with age, meningitis or non-focal bacteraemia, high-risk conditions, and PCV13 serotypes. It is expected that improved PCV13 vaccination coverage in children and an effective PPV23 vaccination strategy in older adults will decrease the incidence and severity of IPD in this age group.
      Ongoing surveillance of all microbiological and clinical data is essential to evaluate the preventive measures available.

      Funding

      This study was partially supported by SpIDnet (Assessing the impact of vaccination with conjugate vaccines on the epidemiology of invasive pneumococcal disease in Europe), a network funded by the European Centre for Disease Prevention and Control ( ECDC/2015/031 ); the Catalan Agency for the Management of Grants for University Research ( AGAUR Grant number 2017/SGR 1342 and 2017/SGR 0742 ); the Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública ( CIBERESP CB06/02/0076 and CB15/00067 ); and the Centro de Investigación Biomédica en Red de Enfermedades Respiratorias ( CIBERES CB06/06/0037 ).

      Conflict of interest

      CMA has received a travel grant from Pfizer. All other authors have no conflicts of interest to declare.

      Author contributions

      PC made substantial contributions to the data collection process as well as to the conception, design, analysis, and interpretation of data, she drafted and revised the manuscript, gave the final approval of the version to be published, and is the corresponding author. SB conducted the statistical analysis. SB, CI, RP, CMA, SH, IG, AD, and MJ made contributions to the interpretation of the data, provided comments on the draft, and read and approved the final version. The other members of the Working Group contributed to data collection, interpretation of the results, and editing the manuscript.

      Acknowledgements

      The members of the Catalan Invasive Pneumococcal Disease Working Group are: P. Ciruela, C. Izquierdo, S. Broner, S. Hernández, M. Jané (Agència de Salut Pública de Catalunya, Barcelona); C. Muñoz-Almagro, C. Esteva, M.F. de Sevilla, D. Henares (Hospital Universitari Sant Joan de Déu, Esplugues – Lab Suport Salut Pública); R. Pallarés, C. Ardanuy, I. Grau (Hospital Universitari de Bellvitge, Hospitalet de Llobregat); F. Marco (Hospital Clínic de Barcelona); N. Margall (Hospital Santa Creu i Sant Pau, Barcelona); A. González-Cuevas (Hospital General Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat); A. Díaz (Fundació Hospital de Nens, Barcelona); M.T. Martin (Hospital Universitari Vall d’Hebron, Barcelona); J. Llaberia (SCIAS Hospital de Barcelona, Barcelona); M. Curriu (Hospital Sant Bernabé, Berga); C. Gallés, E. Capdevila (Corporació de Salut del Maresme i la Selva, Calella); P. Gassiot (Hospital de Figueres, Figueres); M. Martínez-Zurita (Hospital Universitari Dr. Josep Trueta, Girona); C. Martí (Hospital General de Granollers, Granollers); M. Morta (Hospital Sant Joan de Déu, Fundació ALTHAIA, Manresa); G. Sauca (Hospital de Mataró, Mataró); A. Gassós (Hospital Sant Joan de Déu de Martorell, Martorell); E. Sanfeliu (Hospital d’Olot Comarcal de la Garrotxa, Olot); F. Ballester, I. Pujol (Hospital Universitari Sant Joan de Reus, Reus); M. Olsina (Hospital General de Catalunya, Sant Cugat del Vallès); X. Raga (Hospital Sant Pau i Santa Tecla, Tarragona); F. Gómez-Bertomeu (Hospital Joan XXIII, Tarragona); M.O. Pérez-Moreno (Hospital Verge de la Cinta, Tortosa); A. Vilamala, M. Navarro (Hospital Universitari de Vic); M. Ribelles, M. Garcia (Hospital Universitari Arnau de Vilanova de Lleida, Lleida); E. Padilla, N. Prim (Laboratori de Referència Catalunya, Prat de Llobregat); D. Fontanals, I. Sanfeliu (Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, UAB, Sabadell); M.A. Benitez, E. Jou, C. Sanjosé (CLILAB Diagnòstics, Vilafranca del Penedès); M. Giménez, M.D. Quesada (Hospital Universitari Germans Trias i Pujol, Badalona); J.C. de la Fuente (Hospital Comarcal Móra d’Ebre, Mora d’Ebre); A. Calderon (Hospital Municipal de Badalona, Badalona); P.J. Ayala (Clínica Terres de l’Ebre, Tortosa); J. Pérez-Jové, A. Blanco (Catlab-Centre Analítiques Terrassa, AIE, Terrassa); C. Balado, I. Valle (Laboratori d’Anàlisis Dr. F. Echevarne, Barcelona); M.T. Bastida (Fundació Hospital Esperit Sant, Santa Coloma de Gramenet), O. Gonzalez-Moreno (SYNLAB Diagnósticos Globales S.A.U., Esplugues de Llobregat); A. Ubanell (Hospital de Palamós, Palamós).
      We thank A. Fenoll and J. Yuste for serotyping and antibiotic susceptibility testing (Pneumococcal Reference Laboratory, Centro Nacional de Microbiología, ISCIII, Madrid, Spain).

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