Impacto del neumococo y de los virus influenza en niños y adultos : su prevención con vacunas

Contenido principal del artículo

María Hortal

Resumen

Durante siglos las enfermedades infecciosas han diezmado a poblaciones enteras, por lo que se ha procurado descubrir su causa y así lograr su prevención.Actualmente, la vacunación es una de las intervenciones en salud más costo-efectivas para reducir la morbilidad y mortalidad por enfermedades infecciosas. La historia así lo confirma con la erradicación de la viruela, y el control de la poliomielitis y del sarampión a nivel mundial. En Uruguay, el inicio de la vacunación obligatoria contra la viruela se remonta a 1911, en tanto que la vacunación contra la poliomielitis y el sarampión, se implementaron en 1957 y 1966 respectivamente.Dentro de las enfermedades inmunoprevenibles, las infecciones respiratorias agudas son notoriamente las más frecuentes. Su impacto urgió la necesidad de contar con medidas de control. La neumonía, aunque se observa en todas las edades, predomina en los extremos de la vida. En la infancia, en menores de cinco años, es una de las causas más frecuentes de hospitalización y en las poblaciones más desfavorecidas provoca elevada mortalidad. En los adultos con comorbilidades ocurre en todas las edades, pero es más frecuente en los mayores de 65 años, en los que patologías asociadas aumentan el riesgo vital, que es mayor cuanto mayor es la persona. Una vez controladas las neumonías por la vacuna conjugada de Haemophilus influenzae tipo b, el agente bacteriano de mayor frecuencia es Streptococcus pneumoniae y, entre los virus respiratorios, los brotes anuales y las pandemias por virus influenza contribuyen al aumento de hospitalizaciones y decesos por neumonía. Cuando ambos agentes se asocian en un paciente, sus efectos se potencian mutuamente y sus resultados pueden ser fatales. En consecuencia, la prevención de esas infecciones con las vacunas disponibles, neumocóccica y de influenza, es una prioridad de Salud Pública para asegurar la supervivencia infantil y disminuir costos sociales y económicos.

Detalles del artículo

Cómo citar
Hortal, M. (2015). Impacto del neumococo y de los virus influenza en niños y adultos : su prevención con vacunas. Anales De La Facultad De Medicina, Universidad De La República, Uruguay, 2(1), 21-42. Recuperado a partir de http://www.anfamed.edu.uy/index.php/rev/article/view/123
Sección
Artículos de revisión
Biografía del autor/a

María Hortal, Programa de Desarrollo de Ciencias Basicas

Doctora en Medicina, Facultad de Medicina, UdelaR, Uruguay. 

Citas


  1. Centers for Disease Control and Prevention. Prevention of pneumococcal diseases. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1997;46(RR-8).

  2. Centers for Disease Control and Prevention.Vaccine Preventable deaths and the Global Immunization Vision and Strategy, 2006-2015. MMWR. 2006; 55(18):511-5.

  3. Ruocco G, Hortal M. Uruguay. En: Piédrola de Angulos G, coordinador. Universalización de las vacunas. España Portugal y países iberoamericanos. Madrid: Real Academia Nacional de Medicina; 2012. p. 277-98.

  4. Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2000;49(RR-9).

  5. Palacio R, Ruchansky D, Camou T, Alonso R, Goñi N, Baz M, et al. Neumonía aguda comunitaria del adulto hospitalizado : aspectos etiológicos, clínico-terapéuticos y evolutivos. Arch Med Interna. 2007; 29(1):14-20.

  6. Coffey TJ, Enright MC, Daniels M, Morona JK, Morona R, Hryniewicz W, et al. Recombinational exchanges at the capsular polysaccharide biosynthetic locus lead to frequent serotype changes among natural isolates of Streptococcus pneumoniae. Mol Microbiol. 1998 Jan;27(1):73-83.

  7. Avery OT, MacLeod CM, McCarry M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med. 1944;79(2):137-57.

  8. Hansman D, Bullen MM. A resistant pneumococcus. Lancet. 1967;2(7509):264-5. http://dx.doi.org/10.1016/S0140-6736(67)92346-X

  9. Henrichsen J. Typing of Streptococcus pneumoniae: past, present and future. Am J Med. 1999;107(1A):50S-54S.

  10. Henrichsen J. Six newly recognized types of Streptococcus pneumoniae. J Clin Microbiol. 1995; 33(10):2759-62.

  11. Park IH, Park S, Hollingshead SK, Naham MH. Genetic basis for the new pneumococcal serotype 6C. Infec Immun. 2007;75(9):4482-9.

  12. Jedrzejas MJ. Pneumococcal virulence factors: structure and function. Microbiol Mol Biol Rev. 2001;65(2):187-207.

  13. Gramajo S. Variabilidad genética y antigénica de una proteína de la superficie de Streptococcus pneumoniae (PspA) candidata para una vacuna. [Tesis de Maestría no publicada]. Montevideo: PEDECIBA: 2004.

  14. Camou T, Hortal M, Tomasz A. The apparent importation of penicillin-resistant capsular type 14 Spanish/French clone of Streptococcus pneumoniae into Uruguay in the early 1990s. Microb Drug Resist. 1998;4(3):219-24.

  15. Gamboa L, Camou T, Hortal M, Castañeda E; Sireva-Vigía Working Group. Dissemination of Stretococcus pneumoniae Clone Colombia5-19 in Latin America. J Clin Microbiol. 2002;40(11):3042-50. http://dx.doi.org/10.1128/JCM.40.11.3942-3950.2002

  16. Tettelin H, Nelson KE, Paulsen IT, Eisen JA, Read TD, Peterson S, et al. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science. 2001;293(5529):498-506.

  17. Dowson CG ,Barcus V, King S, Pickerill P, Whatmore A, Yeo M. Horizontal gene transfer and the evolution of resistance and virulence determinants in Streptococcus. J Appl Microbiol. 1997;83(S1):42S-52S. http://dx.doi.org/10.1046/j.1365-2672.83.s1.5.x

  18. Gay K, Baughman W, Miller Y, Jackson D, Whitney CG, Schuchat A, et al. The emergence of Streptococcus pneumoniae resistant to macrolide antimicrobial agents: six-year population-based assessment. J Infect Dis. 2000;182(5):1417-24. http://dx.doi.org/10.1086/315853

  19. Camou T. Aspectos clínicamente relevantes de la epidemiología molecular de Streptococcus pneumoniae. [Tesis de Doctorado, no publicada]. Montevideo: PEDECIBA; 2006.

  20. Hortal M, Lovgren M, de la Hoz F, Agudelo CI, Brandileone MC, Camou T, et al. Antibiotic resistance in Streptococcus pneumoniae in six Latin American countries: 1993-1999 surveillance. Microb Drug Resist. 2001;7(4):391-401.

  21. Palacio R, Camou T, Russi JC, Hortal M, Picon T, Nin M, et al. Frequency, type and associated diseases of bacteria and virus in the oropharynx of children born to human immunodeficiency virus-infected mothers. Braz J Infect Dis. 1998; 2(3):128-34.

  22. Austrian R. The enduring pneumococcus: unfinished business and opportunities for the future. Microb Drug Resist. 1997;3(2):111-5.

  23. Lagos R, Di Fabio JL, Moenne K, Muñoz A, Wasserman S, de Quadros C. El uso de la radiografía de tórax para la vigilancia de las neumonías bacterianas en niños latinoamericanos. Rev Panam Salud Pública [Internet]. 2003 [citado 29 jun 2015];13(5):294-301. Disponible en: http://www.scielosp.org/scielo.php?script=sci_arttext http://dx.doi.org/10.1590/S1020-49892003000400004

  24. Flood RG, Badik J, Aronoff SC, The utility of serum C-reactive protein in differentiating bacterial from nonbacterial pneumonia in children:a meta-analysis of 1230 children. Pediatr Infect Dis J. 2008;27(2):97-9. http://dx.doi.org/10.1097/INF.0b013e318157aced

  25. Valenzuela MT, O´Loughlin R, De la Hoz F, Gomez E, Constenla D, Sinha A, et al. The burden of pneumococcal disease among Latin American and Caribbean children: review of the evidence. Rev Panam Salud Pública. 2009;25(3):270-9. http://dx.doi.org/10.1590/S1020-49892009000300011

  26. Di Fabio JL, Homma A, de Quadros C. Pan American Health Organization epidemiological surveillance network for Streptococcus pneumoniae. Microb Drug Resist. 1997;3(2):131-3.

  27. Hortal M, Benitez A, Contera M, Etorena P, Montano A, Meny M. A community-based study of acute respiratory tract infections in children in Uruguay. Rev Infect Dis.1990;12(S8):S966-S73.

  28. Mogdasy MC, Camou T, Fajardo C, Hortal M. Colonizing and invasive strains of Streptococcus pneumoniae in Uruguayan children : type distribution and patterns of antibiotic resistance. Pediatr Infect Dis J. 1992;11(8):648-52.

  29. Camou T, Palacio R, Di Fabio JL, Hortal M. Invasive pneumococcal diseases in Uruguayan children: comparison between serotype distribution and conjugate vaccine formulations. Vaccine. 2003;21(17-18):2093-6.

  30. Hortal M, Estevan M, Iraola I, De Mucio B. A population-based assessment of the disease burden of consolidated pneumonia in hospitalized children under five years of age. Internat J Infect Dis, 2007;11(3):273-7. http://dx.doi.org/10.1016/j.ijid.2006.05.006

  31. Iraola I, Estevan M, Bueno S, Calegari A, Lapides C, Souto G, et al. La neumonía del niño hospitalizado de cinco a catorce años de edad. Arch Pediatr Urug. 2006;76(3):197-201.

  32. Centers for Disease Control and Prevention.Updated recommendations for prevention of invasive pneumococcal disease among adults uing the 23-Valent Pneumococcal Polysaccharide Vaccine (PPSV23). MMWR.2010;59(34):1102-6.

  33. Greenberg RN, Gutman A, Frenk RW, Strout C, Jansen KU, Trammel J, et al. Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naïve adults 60-64 years of age. Vaccine. 2014;32(20):2364-74. http://dx.doi.org/10.1016/j.vaccine.2014.02.002

  34. Fitzwater SP, Chandran A, Santosham M, Johnson HL. The worldwide impact of the seven-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2012;31(5):501-7. http://dx.doi.org/10.1097/INF.0b013e31824de9f6

  35. Andrews NJ, Waight PA, Burbidge P, Pearce E, Roalfe L, Zancolli M, et al. Serotype- specific effectiveness and correlates for the 13-valent pneumococcal conjugate vaccine: a post licensure indirect cohort study. Lancet Infect Dis. 2014;14(9):839-46. http://dx.doi.org/10.1016/S1473-3099(14)70822-9

  36. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Permanente Vaccine Center Group. Pediatr Infect Dis J. 2000;19(3):187-95.

  37. Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al. Efficacy of nine-valent pneumococcal conjugate vaccines against pneumonia and invasive pneumococcal disease in The Gambia: randomized double-blind placebo-controlled trial. Lancet. 2005;365(9465):1139-46.

  38. Pymula R, Peeters P, Chrobok V, Kriz P, Kovakova E, Kaliskova E, et al. Pneumococcal capsular polysaccharides conjugated to protein D for presentation of acute otitis media caused by both Streptococcua pneumoniae and non- typable Haemophilus influenzae: a randomised double- blind efficacy study. Lancet. 2006;367(9512):740-8.

  39. Knuf M, Pankow-Culot H, Grumert  D, Rapp M, Panzer F, Kolger R, et al. Induction of immunologic memory following primary vaccination with 10-valent pneumococcal  nontypeable- Haemophilus influenza protein D conjugate vaccine in infants. Pediatr Infect Dis J. 2012;31(1):e31-36. http://dx.doi.org/10.1097/INF.0b013e3182323ac2

  40. Goldblatt D, Southern J, Ashton L, Richmond P, Burbidge P, Tasevska J, et al. Immunogenicity and boosting after a reduced number of doses of a pneumococcal conjugate vaccine in infants and toddlers. Pediatr Infect Dis J. 2006;25(4):312-9.

  41. Tam I, Madoff LC, Coombes B, Pelton SI. Invasive pneumococcal disease after implementation of 13-valent conjugate vaccine. Pediatrics. 2014;134(2):210-7. http://dx.doi.org/10.1542/peds.2014-0473

  42. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. US. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369(2):155-63. http://dx.doi.org/10.1056/NEJMoa1209165

  43. O´Brien KL, Goldblatt D, Witney CG. Why do we need a systematic review of pneumococcal conjugate vaccine dosing schedules? Pediatr Infect Dis J, 2014;33(Supl 2):S107-8. http://dx.doi.org/10.1097/INF.0000000000000075

  44. Comisión Honoraria para la Lucha Antituberculosa y Enfermedades Prevalentes. Programa Nacional Operativo de Inmunizaciones. Montevideo: CHLAEP. [consultada 2015 jun 29] Disponible en: http://www.chlaep.org.uy/programas.php

  45. Ronveaux O, Arrieta F, Curto S, Laurani H, Danovaro-Holliday MC. Assessment of the quality of immunization data produced by the national individual registration system in Uruguay, 2006. Rev Panam Salud Publica. 2009;26(2):153-60. http://dx.doi.org/10.1590/S1020-49892009000800008

  46. Hortal M, Estevan M, Laurani H, Iraola I. Meny M; Paysandú/Salto Study Group. Hospitalized children with pneumonia in Uruguay: pre and post introduction of 7 and 13-valent pneumococcal conjugated vaccine into the National Immunization Program. Vaccine. 2012;30(33):4934-8. http://dx.doi.org/10.1016/j.vaccine.2012.05.054

  47. Hortal M, Estevan M, Meny M, Iraola I, Laurani H. Impact of pneumococcal conjugate vaccines on the incidence of pneumonia in hospitalized children after five years of its introduction in Uruguay. PLoS ONE [Internet]. 2014 [citado 2015 abr 29];9(6):e98567. http://dx.doi.org/10.1371/journal.pone.0098567

  48. Picón T, Alonso L, García Gabarrot G, Speranza N, Casas M, Arrieta F, et al. Effectivity of the 7-valent pneumococcal conjugate vaccine against vaccine-type invasive disease among children in Uruguay: an evaluation using the existing data. Vaccine. 2013;315(Supl 3):C103-C13. http://dx.doi.org/10.1016/j.vaccine.2013.01.059

  49. Pirez MC, Algorta G, Cedrés A, Sobrero H, Varela A, Giachetto G, et al. Impact of pneumococcal universal vaccination of hospitalizations for pneumonia and meningitis in children in Montevideo, Uruguay. Pediatr Infect Dis J. 2011;30(8):669-7. http://dx.doi.org/10.1097/INF.0b013e3182152bf1.

  50. Hortal M, Meny M, Estevan M, Arrieta F, Lauran H. Effect of 7 and 13-valent pneumococcal conjugate vaccines different number of doses for pneumonia control in 2008 and 2010 birth cohort children. WJV [Internet]. 2015 [citado 2015 abr 29];5(1):37-42. Disponible en: http://www.scirp.org/Journal/PaperInformation.aspx?PaperID=53371#.VUE-JdJ_Oko http://dx.doi.org/10.4236/wjv.2015.51005

  51. Garcia Gabarrot G, López Vega M, Pérez-Giffoni G, Hernández S, Cardinal P, Félix V, et al. Effect of pneumococal conjugate vaccination in Uruguay, a middle-income country. PloS/One [Internet]. 2014 [citado 2015 abr 29];9:1-10. Disponible en: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112337 http://dx.doi.org/10.1371/journal.pone.0112337

  52. Bogaert D, de Groot R. Hermans PM. Streptococcus pneumoniae colonization: the key to pneumococcal disease. Lancet Infect Dis. 2004;4(3):144-53.

  53. Muñoz-Almagro C, Jordan I, Gene A, Latorre C, Garcia Garcia JJ, Pallares R. Emergence of invasive pneumococal disease by nonvaccine serotypes in the era of 7-valent conjugate vaccine. Clin Infect Dis. 2006;46(2):174-83.

  54. Tyrrell GJ. The changing epidemiology of Streptococcus pneumoniae serotype 19A clonal complexes. J Infect Dis. 2011;203(10):1345–7. http://dx.doi.org/10.1093/infdis/jir056

  55. Garcia-Gabarrot G, López Vega M, Perez-Giffoni G, Hortal M, Camou T. Emerging multidrug-resistant clone of Streptococcus pneumoniae serotype 24F/24A in Uruguay after conjugate vaccines introduction [Abstract ISPPD - 0323]. Abstracts of the 9th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-9); 2014 marzo 9-13; Hyderabad, India. Pneumonia [Internet]. 2014 [citado 2015 abr 29];3(Special Issue):204. Disponible en: https://pneumonia.org.au/index.php/pneumonia/issue/view/54/showToc

  56. Ladhani SM, Slack MPE, Andrewa NJ, Waigth PA, Borrow R, Miller E. Invasive pneumococcal disease after routine pneumococcal conjugate vaccination in children , England and Wales. Emerg Infect Dis [Internet]. 2013 [citado 2015 abr 29];19(1):61-8. http://dx.doi.org/10.3201/eid1901.120741

  57. Estevan M, Martínez L, Arreseingor E, Hortal M. Persistance of pleural effusions and empiemas after pneumococcal conjugate vaccine implementation in Uruguay. WJV [Internet]. 2011 [citado 2015 abr 29]; 2(4). Disponible en: http://www.scirp.org/journal/PaperInformation.aspx?PaperID=24804#.VUFKsdJ_Oko http://dx.doi.org/10.4236/wjv.2012.24024

  58. Machado K, Lopez A, Pacheco H, Algorta G, Pirez C. Características del empiema paraneumónico luego del inicio de la vacunación antineumocócica: Centro Hospitalario Pereira Rossell, año 2010. Arch. Pediatr. Urug. 2014;85(4):212-9.

  59. Verhoeven D, Xu Q, Pichichero ME. Vaccination with Streptococcus pneumoniae trivalent recombinant PcpA, PhtD and PlyD1 protein vaccine candidate protects against lethal pneumonia in an infant murine model. Vaccine. 2014;30(26):3205-10. http://dx.doi.org/10.1016/j.vaccine.2014.04.004

  60. Prymula R, Pazdiora P, Traskine M, Ruggeberg JU, Borys D. Safety and immunogenicity of an investiganational vaccine containing two common pneumococcal proteins in toddlers: a fase II ramdomized clinical trial. Vaccine. 2014;32(25):3025-34. http://dx.doi.org/10.1016/j.vaccine.2014.03.066

  61. Odutola A, Antinio M, Ogundare OE, Owaiife P, Worwul A, Greenwood B, et al. Reactogenicity, safety and immunogenicity of a protein-based pneumococcal vaccine in Gambian children aged 2-4 years : fase II randomized study. [Abstract ISPPD - 0407]. Abstracts of the 9th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-9); 2014 marzo 9-13; Hyderabad, India. Pneumonia [Internet]. 2014 [citado 2015 abr 29];3(Special Issue):99. Disponible en: https://pneumonia.org.au/index.php/pneumonia/issue/view/54/showToc

  62. Prymula R, Szenborn SA, Silfverdal J, Wysocki P, Albrecht N, François A, et al. Safety and reactogenicity of two formulations of an investiganotial protein-based pneumococcal vaccine in infants in Europe: a phase II trial. [Abstract ISPPD - 0167]. Abstracts of the 9th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-9); 2014 marzo 9-13; Hyderabad, India. Pneumonia [Internet]. 2014 [citad0 2015 abr 29];3(Special Issue):116. Disponible en: https://pneumonia.org.au/index.php/pneumonia/issue/view/54/showToc

  63. Russi JC, Campione-Picardo J, Hortal M, Osma-Moreira RE, Vallone E, Tosi HC, et al. Infecciones por virus influenza en el niño: primeros aislamientos virales. Arch Pediat Uruguay 1968;39(6):508-13.

  64. Parodi AS, Tosi HC, Stefani M. Un brote de influenza en la ciudad de Montevideo durante el año 1955. Arch Soc Biol Montevideo. 1955;22(1-4):90-2.

  65. Laver G, Bishofberger N, Webster RG. Disarmng the flu viruses. Sci Am. 1999;280(1):56-65.

  66. Bramm J, Ulmanen I, Krug R. Orthomyxoviridae: the virus and their replication. En: Knipe DM, Howley PM, editores. Fields virology. 3a ed. Nueva York: Raven Pres; 1983. p.1353-95.

  67. Gammelin M, Altmuller A, Reinhardt E, Madler J, Harley VR, Hudson PJ, et al. Phylogentic analysis of nucleoprotein suggests that human influenza A viruses emerged from a 19thcentury avian ancestor. Mol Biol Evol. 1990;7(2):194-200.

  68. Wagner R, Matrosovich M, Klenk H. Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol. 2002;12(3):159-66.

  69. Simonsen L, Fekuda K, Schonberger LB, Cox NJ. The impact of influenza epidemics on hospitalizations. J Infect Dis. 2000;181(3):831-7.

  70. Neumann G, Brownlee G, Fodor E, Kawaoka Y. Orthomyxovirus replication , transcription and polyadenylation. Curr Top Microbiol Immunol. 2004;283:121-43.

  71. HeikkimenT, SilvennlnenH, Peltola V. Burden of influenza in children in the community. J Infect Dis. 2004;190:1369-73.

  72. Quian J, Diborboure H, Alvarez R, Gutiérrez S, Aguirre M, Abad L, et al. Cobertura de vacunación antigripal en niños de Montevideo en el año 2010. Arch Pediat Uruguay. 2011;82(4):223-7.

  73. McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev. 2006;19(3):571-82. http://dx.doi.org/10.1128/CMR.00058-05

  74. World Health Organization. Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness [Internet]. s.l: WHO; 2014 [citada 2015 abr 29]. Disponible en: http://www.who.int/influenza/vaccines/virus/201409_zoonotic_vaccinevirusupdate.pdf

  75. Uruguay. Ministerio de Salud Pública. Plan Nacional de Contingencia para una Pandemia de Influenza. [Montevideo]: MSP, 2006.

  76. Gupta RK, George R, Nguyen-Van-Tam JS. Bacterial pneumonia and pandemic influenza planning. Emerg Infect Dis. 2008;14(8):1187-92. http://dx.doi.org/10.3201/eid1408.070751

  77. World Health Organization. Recommended composition of influenza virus vaccines for use in 2015 southern hemisphere influenza season. Wkly Epidemiol Rec [Internet]. 2014 [citado 2015 abr 29];89(41):441-52. Disponible en: http://www.who.int/wer/2014/wer8941.pdf

  78. Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic influenza and pregnant women. Emerg Infect Dis. 2008;14(1):95-9. http://dx.doi.org/10.3201/eid1401.070667

  79. Jefferson T, Smith S, Demicheli V, Harnden A, Rivetti A, Pietnanton CD. Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review. Lancet 2005;365:773-80.

  80. Principi N, Esposito S. Are we ready for universal influenza vaccination in pediatrics? Lancet Infect Dis. 2004;4(2):75-83.

  81. Centers for Disease Control and Prevention. Influenza vaccination coverage among health care personnel, United-States 2013-2014 influenza season. MMWR. 2014;63(37):805-15.

  82. World Health Organization. New influenza A (H1N1) virus: global epidemiological situation. Wkly Epidemiol Rec [Internet] . 2009 [citado 2015 abr 29] ;84(25):249-57. Disponible en: http://www.who.int/wer/2009/wer8425.pdf

  83. Jefferson T, Demicheli V, Deeks J, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev. 2000;(2):CD001265.

  84. Bernstein DI, Yan L, Treanor J, Mendelman PM, Belshe R; Cold-Adapted, Trivalent, Influenza Vaccine Study Group. Effect of yearly vaccinations with live, attenuated, cold-adapted, trivalent, intranasal influenza vaccines on antibody responses in children. Pediatr Infect Dis J. 2003; 22(1):28-34.

  85. Goñi N. Variabilidad genética del virus influenza B en Uruguay. [Tesis de Maestría, no publicada]. Montevideo: PEDECIBA; 2006.

  86. Treanor JJ. Expanding the options for confronting pandemic influenza. JAMA (Comentario editorial). 2014 Oct 8;312(14):1401-2. http://dx.doi.org/10.1001/jama.2014.12558. Comentario sobre: Mulligan MJ, Bernstein DI, Winokur P, Rupp R, Anderson E, Rouphael N, et al. Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant: a randomized clinical trial. JAMA. 2014 Oct 8;312(14):1409-19. http://dx.doi.org/10.1001/jama.2014.12854

  87. Centers for Disease Control and Prevention. Interim guidance for protection of persons involved in U.S. avian influenza outbreak disease control and protection, US. [Internet]. Department of Health and Human Services, CDC: 2006. [citada 2015 abr 29]. Disponible en: http://www.cdc.gov/flu/avian/professional/protect-guid.htm

  88. Hortal M, Arbiza JR. Pneumococcal and influenza vaccines: a synergistic effect? [Carta]. Pediatric Infect Dis J. 2007;26(10):969.

  89. O´Brien KL, Walters MI, Sellman J, Quinlisk P, Regnery H, Schwartz B, et al. Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection. Clin Infect Dis. 2000;30(5):784-9.

  90. Peltola VT, Gopal Murti K, McCullers JA. The influenza virus neuraminidase contributes to secondary bacterial pneumonia. J Infect Dis. 2005;192(2):249–57. http://dx.doi.org/10.1086/430954

  91. Brundage JF. Interaction between influenza and bacterial respiratory pathogens: implications for pandemic preparedness. Lancet Infect Dis. 2006;6(5):303-11.

  92. Zhou H, Haber M, Ray S, Farley M, Panozzo CA, Klugman KP. Invasive pneumococcal pneumonia and respiratory virus co-infections. Emerg Infect Dis. 2012;18(2):294-7. http://dx.doi.org/10.3201/eid1802.102025