Influenza Infection in the Elderly

  • Kasra Moazzami
  • Janet E. McElhaney
  • Nima RezaeiEmail author


Influenza is a febrile respiratory disease, which is usually associated with a mild acute self-limited illness. However, certain risk factors, including ageing, are associated with severity of disease and the occurrence of influenza-related complications. Influenza infection has shown to be foremost among all infectious diseases in its association with an age-related increase in the incidence of serious complications. A decrease in immune function is a hallmark of ageing that imposes negative effects in its ability to resist influenza virus infection and its response to vaccination. It has been recognized that the ageing process affects both branches of the immune system, namely, the innate and adaptive immune systems.


Major Histocompatibility Complex Natural Killer Cell Influenza Vaccine Influenza Vaccination Influenza Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Agrawal A, Agrawal S, Gupta S (2007) Dendritic cells in human aging. Exp Gerontol 42(5):421–426PubMedCrossRefGoogle Scholar
  2. Aspinall R, Henson S, Pido-Lopez J et al (2004) Interleukin-7: an interleukin for rejuvenating the immune system. Ann N Y Acad Sci 1019:116–122PubMedCrossRefGoogle Scholar
  3. Aydar Y, Balogh P, Tew JG et al (2002) Age-related depression of FDC accessory functions and CD21 ligand-mediated repair of co-stimulation. Eur J Immunol 32(10):2817–2826PubMedCrossRefGoogle Scholar
  4. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392(6673):245–252PubMedCrossRefGoogle Scholar
  5. Barker WH, Borisute H, Cox C (1998) A study of the impact of influenza on the functional status of frail older people. Arch Intern Med 158(6):645–650PubMedCrossRefGoogle Scholar
  6. Behzad H, Huckriede AL, Haynes L et al (2012) GLA-SE, a synthetic toll-like receptor 4 agonist, enhances T-cell responses to influenza vaccine in older adults. J Infect Dis 205(3):466–473PubMedCrossRefGoogle Scholar
  7. Bender BS, Small PA Jr (1993) Heterotypic immune mice lose protection against influenza virus infection with senescence. J Infect Dis 168(4):873–880PubMedCrossRefGoogle Scholar
  8. Blasco MA, Funk W, Villeponteau B et al (1995) Functional characterization and developmental regulation of mouse telomerase RNA. Science 269(5228):1267–1270PubMedCrossRefGoogle Scholar
  9. Bleackley RC, Lobe CG, Duggan B et al (1988) The isolation and characterization of a family of serine protease genes expressed in activated cytotoxic T lymphocytes. Immunol Rev 103:5–19PubMedCrossRefGoogle Scholar
  10. Borrego F, Alonso MC, Galiani MD et al (1999) NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol 34(2):253–265PubMedCrossRefGoogle Scholar
  11. Brown LK (1994) Respiratory dysfunction in Parkinson’s disease. Clin Chest Med 15(4):715–727PubMedGoogle Scholar
  12. Butcher S, Chahel H, Lord JM (2000) Review article: ageing and the neutrophil: no appetite for killing? Immunology 100(4):411–416PubMedCrossRefGoogle Scholar
  13. Carrat F, Flahault A (2007) Influenza vaccine: the challenge of antigenic drift. Vaccine 25(39–40):6852–6862PubMedCrossRefGoogle Scholar
  14. Chatta GS, Andrews RG, Rodger E et al (1993) Hematopoietic progenitors and aging: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J Gerontol 48(5):M207–M212PubMedCrossRefGoogle Scholar
  15. Colonna-Romano G, Bulati M, Aquino A et al (2003) B cells in the aged: CD27, CD5, and CD40 expression. Mech Ageing Dev 124(4):389–393PubMedCrossRefGoogle Scholar
  16. Covinsky KE, Palmer RM, Fortinsky RH et al (2003) Loss of independence in activities of daily living in older adults hospitalized with medical illnesses: increased vulnerability with age. J Am Geriatr Soc 51(4):451–458PubMedCrossRefGoogle Scholar
  17. Deans GD, Stiver HG, McElhaney JE (2010) Influenza vaccines provide diminished protection but are cost-saving in older adults. J Intern Med 267(2):220–227PubMedCrossRefGoogle Scholar
  18. Demotz S, Grey HM, Sette A (1990) The minimal number of class II MHC-antigen complexes needed for T cell activation. Science 249(4972):1028–1030PubMedCrossRefGoogle Scholar
  19. Doherty PC, Topham DJ, Tripp RA et al (1997) Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol Rev 159:105–117PubMedCrossRefGoogle Scholar
  20. Drinka PJ, Krause P, Nest L (2003) Clinical features of influenza a virus infection in older hospitalized persons. J Am Geriatr Soc 51(8):1184PubMedCrossRefGoogle Scholar
  21. Dumont FJ, Staruch MJ, Fischer P et al (1998) Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. J Immunol 160(6):2579–2589PubMedGoogle Scholar
  22. Effros RB (2007) Role of T lymphocyte replicative senescence in vaccine efficacy. Vaccine 25(4):599–604PubMedCrossRefGoogle Scholar
  23. Effros RB, Doherty PC, Gerhard W et al (1977) Generation of both cross-reactive and virus-specific T-cell populations after immunization with serologically distinct influenza A viruses. J Exp Med 145(3):557–568PubMedCrossRefGoogle Scholar
  24. Effros RB, Dagarag M, Spaulding C et al (2005) The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 205:147–157PubMedCrossRefGoogle Scholar
  25. Evans SA, Watson L, Hawkins M et al (1995) Respiratory muscle strength in chronic heart failure. Thorax 50(6):625–628PubMedCrossRefGoogle Scholar
  26. Ewen C, Kane KP, Shostak I et al (2003) A novel cytotoxicity assay to evaluate antigen-specific CTL responses using a colorimetric substrate for Granzyme B. J Immunol Methods 276(1–2):89–101PubMedCrossRefGoogle Scholar
  27. Fadok VA, Bratton DL, Konowal A et al (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101(4):890–898PubMedCrossRefGoogle Scholar
  28. Falsey AR, Hennessey PA, Formica MA et al (2005) Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 352(17):1749–1759PubMedCrossRefGoogle Scholar
  29. Fiore AE, Shay DK, Broder K et al (2009) Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 58(RR-8):1–52PubMedGoogle Scholar
  30. Franceschi C, Bonafe M, Valensin S (2000) Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18(16):1717–1720PubMedCrossRefGoogle Scholar
  31. Frasca D, Landin AM, Lechner SC et al (2008) Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol 180(8):5283–5290PubMedGoogle Scholar
  32. Frasca D, Diaz A, Romero M et al (2011) Age effects on B cells and humoral immunity in humans. Ageing Res Rev 10(3):330–335PubMedCrossRefGoogle Scholar
  33. Fulop T Jr, Foris G, Worum I et al (1985) Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes. Clin Exp Immunol 61(2):425–432PubMedGoogle Scholar
  34. Gomez CR, Boehmer ED, Kovacs EJ (2005) The aging innate immune system. Curr Opin Immunol 17(5):457–462PubMedCrossRefGoogle Scholar
  35. Goronzy JJ, Weyand CM (2005) T cell development and receptor diversity during aging. Curr Opin Immunol 17(5):468–475PubMedCrossRefGoogle Scholar
  36. Goronzy JJ, Fulbright JW, Crowson CS et al (2001) Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75(24):12182–12187PubMedCrossRefGoogle Scholar
  37. Gorse GJ, O’Connor TZ, Newman FK et al (2004) Immunity to influenza in older adults with chronic obstructive pulmonary disease. J Infect Dis 190(1):11–19PubMedCrossRefGoogle Scholar
  38. Govaert TM, Thijs CT, Masurel N et al (1994) The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial. JAMA 272(21):1661–1665PubMedCrossRefGoogle Scholar
  39. Granucci F, Zanoni I, Feau S et al (2003) Dendritic cell regulation of immune responses: a new role for interleukin 2 at the intersection of innate and adaptive immunity. EMBO J 22(11):2546–2551PubMedCrossRefGoogle Scholar
  40. Grolleau-Julius A, Harning EK, Abernathy LM et al (2008) Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res 68(15):6341–6349PubMedCrossRefGoogle Scholar
  41. Ito T, Gorman OT, Kawaoka Y et al (1991) Evolutionary analysis of the influenza A virus M gene with comparison of the M1 and M2 proteins. J Virol 65(10):5491–5498PubMedGoogle Scholar
  42. Janssens JP, Krause KH (2004) Pneumonia in the very old. Lancet Infect Dis 4(2):112–124PubMedCrossRefGoogle Scholar
  43. Jenne DE, Tschopp J (1988) Granzymes, a family of serine proteases released from granules of cytolytic T lymphocytes upon T cell receptor stimulation. Immunol Rev 103:53–71PubMedCrossRefGoogle Scholar
  44. Kohler S, Wagner U, Pierer M et al (2005) Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol 35(6):1987–1994PubMedCrossRefGoogle Scholar
  45. Kronenberg RS, Drage CW (1973) Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men. J Clin Invest 52(8):1812–1819PubMedCrossRefGoogle Scholar
  46. Lalvani A, Dong T, Ogg G et al (1997) Optimization of a peptide-based protocol employing IL-7 for in vitro restimulation of human cytotoxic T lymphocyte precursors. J Immunol Methods 210(1):65–77PubMedCrossRefGoogle Scholar
  47. Lazuardi L, Jenewein B, Wolf AM et al (2005) Age-related loss of naive T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes. Immunology 114(1):37–43PubMedCrossRefGoogle Scholar
  48. Loeb M (2003) Pneumonia in older persons. Clin Infect Dis 37(10):1335–1339PubMedCrossRefGoogle Scholar
  49. Marcelin G, DuBois R, Rubrum A et al (2012) A contributing role for anti-neuraminidase antibodies on immunity to pandemic H1N1 2009 influenza A virus. PLoS One 6(10):26335CrossRefGoogle Scholar
  50. McElhaney JE (2005) The unmet need in the elderly: designing new influenza vaccines for older adults. Vaccine 23(Suppl 1):S10–S25PubMedCrossRefGoogle Scholar
  51. McElhaney JE (2008) Influenza vaccination in the elderly: seeking new correlates of protection and improved vaccines. Aging health 4(6):603–613PubMedCrossRefGoogle Scholar
  52. McElhaney JE (2009) Prevention of infectious diseases in older adults through immunization: the challenge of the senescent immune response. Expert Rev Vaccines 8(5):593–606PubMedCrossRefGoogle Scholar
  53. McElhaney JE (2011) Influenza vaccine responses in older adults. Ageing Res Rev 10(3):379–388PubMedCrossRefGoogle Scholar
  54. McElhaney JE, Dutz JP (2008) Better influenza vaccines for older people: what will it take? J Infect Dis 198(5):632–634PubMedCrossRefGoogle Scholar
  55. McElhaney JE, Effros RB (2009) Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 21(4):418–424PubMedCrossRefGoogle Scholar
  56. McElhaney JE, Gravenstein S, Upshaw CM et al (2001) Granzyme B: a marker of risk for influenza in institutionalized older adults. Vaccine 19(27):3744–3751PubMedCrossRefGoogle Scholar
  57. McElhaney JE, Xie D, Hager WD et al (2006) T cell responses are better correlates of vaccine protection in the elderly. J Immunol 176(10):6333–6339PubMedGoogle Scholar
  58. McElhaney JE, Ewen C, Zhou X et al (2009) Granzyme B: correlates with protection and enhanced CTL response to influenza vaccination in older adults. Vaccine 27(18):2418–2425PubMedCrossRefGoogle Scholar
  59. McElhaney JE, Zhou X, Talbot HK et al (2012) The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine 30(12):2060–2067PubMedCrossRefGoogle Scholar
  60. McKenna RW, Washington LT, Aquino DB et al (2001) Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood 98(8):2498–2507PubMedCrossRefGoogle Scholar
  61. McMichael AJ, Gotch FM, Noble GR et al (1983) Cytotoxic T-cell immunity to influenza. N Engl J Med 309(1):13–17PubMedCrossRefGoogle Scholar
  62. Meyer KC, Ershler W, Rosenthal NS et al (1996) Immune dysregulation in the aging human lung. Am J Respir Crit Care Med 153(3):1072–1079PubMedCrossRefGoogle Scholar
  63. Miller C, Kelsoe G (1995) Ig VH hypermutation is absent in the germinal centers of aged mice. J Immunol 155(7):3377–3384PubMedGoogle Scholar
  64. Miyaji C, Watanabe H, Toma H et al (2000) Functional alteration of granulocytes, NK cells, and natural killer T cells in centenarians. Hum Immunol 61(9):908–916PubMedCrossRefGoogle Scholar
  65. Molinari NA, Ortega-Sanchez IR, Messonnier ML et al (2007) The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 25(27):5086–5096PubMedCrossRefGoogle Scholar
  66. Molling JW, Kolgen W, van der Vliet HJ et al (2005) Peripheral blood IFN-gamma-secreting Valpha24 + Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer 116(1):87–93PubMedCrossRefGoogle Scholar
  67. Monto AS, Ansaldi F, Aspinall R et al (2009) Influenza control in the 21st century: optimizing protection of older adults. Vaccine 27(37):5043–5053PubMedCrossRefGoogle Scholar
  68. Mullooly JP, Bennett MD, Hornbrook MC et al (1994) Influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organization. Ann Intern Med 121(12):947–952PubMedCrossRefGoogle Scholar
  69. Nichol KL, Margolis KL, Wuorenma J et al (1994) The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med 331(12):778–784PubMedCrossRefGoogle Scholar
  70. Nomellini V, Gomez CR, Kovacs EJ (2008) Aging and impairment of innate immunity. Contrib Microbiol 15:188–205PubMedGoogle Scholar
  71. Nordin J, Mullooly J, Poblete S et al (2001) Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: data from 3 health plans. J Infect Dis 184(6):665–670PubMedCrossRefGoogle Scholar
  72. Pasternack MS, Eisen HN (1985) A novel serine esterase expressed by cytotoxic T lymphocytes. Nature 314(6013):743–745PubMedCrossRefGoogle Scholar
  73. Plackett TP, Boehmer ED, Faunce DE et al (2004) Aging and innate immune cells. J Leukoc Biol 76(2):291–299PubMedCrossRefGoogle Scholar
  74. Plowden J, Renshaw-Hoelscher M, Engleman C et al (2004) Innate immunity in aging: impact on macrophage function. Aging Cell 3(4):161–167PubMedCrossRefGoogle Scholar
  75. Reichert TA, Simonsen L, Sharma A et al (2004) Influenza and the winter increase in mortality in the United States, 1959–1999. Am J Epidemiol 160(5):492–502PubMedCrossRefGoogle Scholar
  76. Rimmelzwaan GF, McElhaney JE (2008) Correlates of protection: novel generations of influenza vaccines. Vaccine 26(Suppl 4):D41–D44PubMedCrossRefGoogle Scholar
  77. Rock KL, Shen L (2005) Cross-presentation: underlying mechanisms and role in immune surveillance. Immunol Rev 207:166–183PubMedCrossRefGoogle Scholar
  78. Rouvier E, Luciani MF, Golstein P (1993) Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J Exp Med 177(1):195–200PubMedCrossRefGoogle Scholar
  79. Sambhara S, McElhaney JE (2009) Immunosenescence and influenza vaccine efficacy. Curr Top Microbiol Immunol 333:413–429PubMedGoogle Scholar
  80. Saurwein-Teissl M, Lung TL, Marx F et al (2002) Lack of antibody production following immunization in old age: association with CD8(+)CD28(−) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol 168(11):5893–5899PubMedGoogle Scholar
  81. Shahid Z, Kleppinger A, Gentleman B et al (2010) Clinical and immunologic predictors of influenza illness among vaccinated older adults. Vaccine 28(38):6145–6151PubMedCrossRefGoogle Scholar
  82. Shi Y, Yamazaki T, Okubo Y et al (2005) Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J Immunol 175(5):3262–3267PubMedGoogle Scholar
  83. Skowronski DM, Hottes TS, McElhaney JE et al (2011) Immuno-epidemiologic correlates of pandemic H1N1 surveillance observations: higher antibody and lower cell-mediated immune responses with advanced age. J Infect Dis 203(2):158–167PubMedCrossRefGoogle Scholar
  84. Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18(16):1613–1620PubMedCrossRefGoogle Scholar
  85. Solana R, Alonso MC, Pena J (1999) Natural killer cells in healthy aging. Exp Gerontol 34(3):435–443PubMedCrossRefGoogle Scholar
  86. Spaulding C, Guo W, Effros RB (1999) Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 34(5):633–644PubMedCrossRefGoogle Scholar
  87. Steger MM, Maczek C, Berger P et al (1996) Vaccination against tetanus in the elderly: do recommended vaccination strategies give sufficient protection. Lancet 348(9029):762PubMedCrossRefGoogle Scholar
  88. Thompson WW, Shay DK, Weintraub E et al (2003) Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289(2):179–186PubMedCrossRefGoogle Scholar
  89. Thompson WW, Shay DK, Weintraub E et al (2004) Influenza-associated hospitalizations in the United States. JAMA 292(11):1333–1340PubMedCrossRefGoogle Scholar
  90. Tolep K, Kelsen SG (1993) Effect of aging on respiratory skeletal muscles. Clin Chest Med 14(3):363–378PubMedGoogle Scholar
  91. Turner DA, Wailoo AJ, Cooper NJ et al (2006) The cost-effectiveness of influenza vaccination of healthy adults 50–64 years of age. Vaccine 24(7):1035–1043PubMedCrossRefGoogle Scholar
  92. Vallejo AN (2005) CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev 205:158–169PubMedCrossRefGoogle Scholar
  93. Van der Sluijs KF, van Elden LJ, Nijhuis M et al (2004) IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J Immunol 172(12):7603–7609PubMedGoogle Scholar
  94. Vescovini R, Biasini C, Fagnoni FF et al (2007) Massive load of functional effector CD4+ and CD8+ T cells against cytomegalovirus in very old subjects. J Immunol 179(6):4283–4291PubMedGoogle Scholar
  95. Virelizier JL, Allison AC, Schild GC (1974) Antibody responses to antigenic determinants of influenza virus hemagglutinin. II. Original antigenic sin: a bone marrow-derived lymphocyte memory phenomenon modulated by thymus-derived lymphocytes. J Exp Med 140(6):1571–1578PubMedCrossRefGoogle Scholar
  96. Wagar LE, Gentleman B, Pircher H et al (2011) Influenza-specific T cells from older people are enriched in the late effector subset and their presence inversely correlates with vaccine response. PLoS One 6(8):e23698PubMedCrossRefGoogle Scholar
  97. Wenisch C, Patruta S, Daxbock F et al (2000) Effect of age on human neutrophil function. J Leukoc Biol 67(1):40–45PubMedGoogle Scholar
  98. Whitley RJ, Monto AS (2006) Prevention and treatment of influenza in high-risk groups: children, pregnant women, immunocompromised hosts, and nursing home residents. J Infect Dis 194(Suppl 2):S133–S138PubMedCrossRefGoogle Scholar
  99. Zhou X, McElhaney JE (2011) Age-related changes in memory and effector T cells responding to influenza A/H3N2 and pandemic A/H1N1 strains in humans. Vaccine 29(11):2169–2177PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kasra Moazzami
    • 1
  • Janet E. McElhaney
    • 2
  • Nima Rezaei
    • 3
    • 4
    • 5
    Email author
  1. 1.Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical SchoolCharlestownUSA
  2. 2.Vancouver Coastal Health Research InstituteUniversity of British ColumbiaVancouverCanada
  3. 3.Research Center for Immunodeficiencies, Children’s Medical CenterTehran University of Medical SciencesTehranIran
  4. 4.Department of Immunology, School of MedicineTehran University of Medical SciencesTehranIran
  5. 5.Molecular Immunology Research CenterTehran University of Medical SciencesTehranIran

Personalised recommendations