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Age-specific estimates of US influenza-associated deaths and hospitalizations
International Congress Series 1263 (2004) 316 – 320
www.ics-elsevier.com
Age-specific estimates of US influenza-associated deaths and hospitalizations William W. Thompson *, Eric Weintraub, David K. Shay, Lynnette Brammer, Nancy Cox, Keiji Fukuda US Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., MS E-61, Atlanta, GA 30333, USA
Abstract. We estimated annual numbers and rates of influenza-associated deaths and hospitalizations by age group in the United States using a Poisson regression model incorporating World Health Organization (WHO) viral surveillance data. Mortality data were obtained between 1976 and 2000 from the National Center for Health Statistics (NCHS); hospitalization data were obtained between 1979 and 2001 from the National Hospital Discharge Survey (NHDS). Weekly influenza isolates by type and subtype were obtained from the WHO collaborating laboratories for the 1976 – 1977 through 1999 – 2000 seasons. Our models estimated annual averages of 6796 underlying pneumonia and influenza deaths and 28,076 underlying respiratory and circulatory deaths. The models estimated annual averages of 88,479 primary pneumonia and influenza hospitalizations and 225,985 primary respiratory and circulatory hospitalizations. We found significant increases in the numbers of influenza-associated deaths and hospitalizations by year among persons aged z65 years due to the aging of the population, the predominance of A(H3N2) viruses during the late 1990s and the increasing length of the influenza season during the 1990s. D 2004 Elsevier B.V. All rights reserved. Keywords: Influenza hospitalizations; Deaths models
1. Introduction In the United States, the Centers for Disease Control and Prevention (CDC) is responsible for providing national annual estimates of the burden of disease for influenza [1– 5]. Monitoring deaths and hospitalizations associated with influenza is important for planning annual resource needs associated with influenza epidemics and for determining costs and benefits associated with alternative influenza prevention and control strategies [6 –8]. Three influenza pandemics occurred during the 2000 century: the 1918 – 1920 A(H1N1) pandemic, the 1957 – 1960 A(H2N2) pandemic, and the 1968 –1972 A(H3N2) pandemic. These three influenza pandemics were associated with annual U.S. all-cause deaths of 225,000; 38,567 and 27,982, respectively, and deaths rates of 218, 22, and 14 deaths per 100,000 person-years, respectively [9]. The CDC estimates that influenza * Corresponding author. Tel.: +1-404-639-8896; fax: +1-404-639-8834. E-mail address: [email protected] (W.W. Thompson). 0531-5131/ D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.02.072
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317
viruses currently are associated with 36,000 respiratory and circulatory deaths annually [5]. Thus, annual deaths associated with influenza viruses in the United States actually exceed the numbers of annual deaths associated with the A(H3N2) pandemic, due in large part to the aging of the population [5]. Three methods have been used by CDC to estimate influenza-associated deaths and hospitalizations: rate-difference models [10 – 12], linear regression models, which do not incorporate viral data [2,3,13,14] and Poisson regression models, which incorporate viral data [5,15]. In this paper, we use Poisson regression models to provide updates of the estimates of annual numbers and rates of influenza-associated deaths and hospitalizations in the United States by age group. 2. Materials and methods Weekly influenza isolates by type and subtype were obtained from WHO collaborating laboratories for the 1976 –1977 through 1999 –2001 seasons. Mortality data were obtained from the NCHS and hospital data from the NHDS. Pneumonia and influenza hospitalizations and deaths were modeled by using ICD-9 codes, 480 –487, and ICD-10 codes, J10-J18. Respiratory and circulatory hospitalizations and deaths were modeled by using ICD-9 codes, 390 –519, and ICD-10 codes, I00 –I99 and J00 – J99. The CDC mortality model uses weekly mortality data and applies an age-specific Poisson regression model, Yij=a exp(b0+b1 [t]+b2 [t2]+b3 [sin(2pt/52)]+b4 [cos(2pt/ 52)]+b5 [A(H1N1)]+b6 [A(H3N2)]+b7 [B]), where Yij is the number of weekly deaths for outcome i in age group j, b0 is the intercept, b1 is a linear time trend, b2 is a quadratic time trend, b3 and b4 are cyclical changes in deaths, and b5 – b7 are the national percentages of specimens testing positive for influenza types/subtypes each week. The CDC hospitalization model uses a similar Poisson regression model, but uses monthly data for hospitalizations and viral terms. 3. Results 3.1. Annual estimates of influenza-associated deaths and hospitalizations in the United States From the 1976 –1977 through the 1999 –2000 respiratory seasons, we estimated that an annual average of 6796 (range 927– 14,556) pneumonia and influenza deaths and 28,076 (range 4348 – 53,616) respiratory and circulatory deaths were associated with the circulation of influenza viruses (Table 1). From the 1979 – 1980 through the 2000 –2001 respiratory seasons, we estimated that an annual average of 88,479 (range 19,666 – 208,173) pneumonia and influenza and 225,985 (range 65,300 –456,480) respiratory and circulatory hospitalizations were associated with influenza viruses. 3.2. Annual age-specific estimates of rates of influenza-associated deaths and hospitalizations in the United States In the United States, 2.5 underlying pneumonia and influenza deaths per 100,000 persons were associated with influenza viruses during the 1976 –1977 and 1999– 2000 respiratory seasons, while 10.7 underlying respiratory and circulatory deaths per 100,000
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W.W. Thompson et al. / International Congress Series 1263 (2004) 316–320
Table 1 Annual influenza-associated deaths and hospitalizations in the US Season
Influenza-associated deaths
Influenza-associated hospitalizations
Underlying P&I
Underlying R&C
Primary P&I
Primary R&C
1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Average
2073 4304 927 2016 3939 1092 5528 3059 8450 4218 1176 5124 4624 8079 3967 9169 6751 9527 7511 6275 13,271 14,556 14,426 9949 NA 6796
12,955 26,527 4348 10,265 22,228 5358 29,064 13,739 40,651 18,901 4444 23,506 18,054 34,944 16,168 37,582 27,228 37,977 30,046 25,010 50,039 53,616 52,273 38,513 NA 28,076
NA NA NA 47,022 35,356 22,353 55,934 56,878 86,332 65,695 19,666 57,387 82,494 79,035 93,902 80,848 119,678 89,734 99,574 99,932 148,418 167,599 208,173 142,635 87,889 88,479
NA NA NA 134,670 146,069 65,300 203,506 161,452 287,926 160,359 68,022 168,165 195,593 224,917 206,154 224,280 261,283 234,698 237,987 243,432 336,377 404,970 456,480 367,136 182,881 225,985
persons were associated with influenza (Table 2). In each category, rates of influenzaassociated deaths increased exponentially with increasing age. Persons agedz85 years were 32 times more likely to die from pneumonia and influenza compared with persons 65– 69 years, while those agedz85 years were 19 times more likely to experience a respiratory and circulatory death compared with those aged 65– 69 years. Approximately 35 pneumonia and influenza hospitalizations per 100,000 persons were associated with influenza viruses during the 1979 –1980 and 2000 – 2001 respiratory Table 2
Age-specific influenza-associated deaths and hospitalization rates Age group (years)
0–4 5 – 49 50 – 64 65 – 69 70 – 74 75 – 79 80 – 84 85+ Total a
Influenza-associated deaths ratesa
Influenza-associated hospitalization ratesa
Underlying P&I
Underlying R&C
Primary P&I
Primary R&C
0.2 0.2 1.1 3.0 5.9 12.2 29.7 97.9 2.5
0.5 0.3 6.2 18.6 32.8 64.7 127.4 351.4 10.7
14 5 35 56 134 213 307 652 35
118 21 88 168 365 464 679 1257 90
Rates per 100,00 person years.
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Fig. 1. Age-specific relative ratios of hospitalization rates to death rates.
seasons; 90 respiratory and circulatory hospitalizations per 100,000 persons were associated with influenza. Persons aged z85 years were 12 times more likely to be hospitalized with pneumonia and influenza compared with those 65– 69 years, and persons aged z85 years were seven times more likely to be hospitalized with a respiratory and circulatory condition compared with persons 65– 69 years. Children <5 years were at much greater risk for an influenza-associated hospitalization compared with an influenza-associated death (Fig. 1). In contrast, persons aged z85 years were almost as likely to die an influenza-associated death as they were to be hospitalized with an influenza-associated condition. 4. Discussion We estimated annual numbers and rates of influenza-associated deaths and hospitalizations in the United States by using more specific age groups than have previous studies. We demonstrated that both influenza-associated deaths and hospitalizations among persons aged z65 years have increased substantially in the US, likely due to the aging of the population, the predominance of A(H3N2) viruses during the late 1990s, and the increasing length of influenza seasons during the 1990s. Most influenza-associated hospitalizations and deaths occur among the elderly, and vaccinating the elderly will continue to be the primary strategy for preventing influenza-associated deaths and hospitalizations in this group [8]. Many studies [7,16] comparing outcomes in vaccinated with unvaccinated groups have shown that the currently available trivalent, inactivated influenza vaccine is effective in preventing both deaths and hospitalizations associated with influenza infections. Given the increasing numbers of influenza-associated hospitalizations and deaths among the elderly, several immunization strategies are currently being assessed to determine whether they may be more cost effective [17,18].
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W.W. Thompson et al. / International Congress Series 1263 (2004) 316–320
References [1] T.C. Eickhoff, I.L. Sherman, R.E. Serfling, Observations on excess mortality associated with epidemic influenza, JAMA 176 (1961) 776 – 782. [2] R.E. Serfling, Methods for current statistical analysis of excess pneumonia-influenza deaths, Public Health Rep. 78 (6) (1963) 494 – 505. [3] K.J. Lui, A.P. Kendal, Impact of influenza epidemics on mortality in the United States from October 1972 to May 1985, Am. J. Public Health 77 (6) (1987) 712 – 716. [4] L. Simonsen, et al., The impact of influenza epidemics on hospitalizations, J. Infect. Dis. 181 (3) (2000) 831 – 837. [5] W.W. Thompson, et al., Mortality associated with influenza and respiratory syncytial virus in the United States, JAMA 289 (2) (2003) 179 – 186. [6] M.I. Meltzer, N.J. Cox, K. Fukuda, The economic impact of pandemic influenza in the United States: priorities for intervention, Emerg. Infect. Dis. 5 (5) (1999) 659 – 671. [7] K.L. Nichol, The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines, Vaccine 21 (16) (2003) 1769 – 1775. [8] C.B. Bridges, et al., Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm. Rep. 52 (RR-8) (2003) 1 – 34. [9] W.P. Glezen, Emerging infections: pandemic influenza, Epidemiol. Rev. 18 (1) (1996) 64 – 76. [10] W.H. Barker, J.P. Mullooly, Impact of epidemic type A influenza in a defined adult population, Am. J. Epidemiol. 112 (6) (1980) 798 – 811. [11] W.H. Barker, J.P. Mullooly, Pneumonia and influenza deaths during epidemics: implications for prevention, Arch. Intern. Med. 142 (1) (1982) 85 – 89. [12] H.S. Izurieta, et al., Influenza and the rates of hospitalization for respiratory disease among infants and young children, N. Engl. J. Med. 342 (4) (2000) 232 – 239. [13] K. Choi, S.B. Thacker, An evaluation of influenza mortality surveillance, 1962 – 1979: I. Time series forecasts of expected pneumonia and influenza deaths, Am. J. Epidemiol. 113 (3) (1981) 215 – 226. [14] L. Simonsen, et al., The impact of influenza epidemics on mortality: introducing a severity index, Am. J. Public Health 87 (12) (1997) 1944 – 1950. [15] K.M. Neuzil, et al., Winter respiratory viruses and health care use: a population-based study in the northwest United States, Clin. Infect. Dis. 37 (2) (2003) 201 – 207. [16] P.A. Gross, et al., The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature, Ann. Intern. Med. 123 (7) (1995) 518 – 527. [17] T.A. Reichert, et al., The Japanese experience with vaccinating schoolchildren against influenza, N. Engl. J. Med. 344 (12) (2001) 889 – 896. [18] I.M. Longini, et al., Estimation of the efficacy of live, attenuated influenza vaccine from a two-year, multicenter vaccine trial: implications for influenza epidemic control, Vaccine 18 (18) (2000) 1902 – 1909.
www.ics-elsevier.com
Age-specific estimates of US influenza-associated deaths and hospitalizations William W. Thompson *, Eric Weintraub, David K. Shay, Lynnette Brammer, Nancy Cox, Keiji Fukuda US Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., MS E-61, Atlanta, GA 30333, USA
Abstract. We estimated annual numbers and rates of influenza-associated deaths and hospitalizations by age group in the United States using a Poisson regression model incorporating World Health Organization (WHO) viral surveillance data. Mortality data were obtained between 1976 and 2000 from the National Center for Health Statistics (NCHS); hospitalization data were obtained between 1979 and 2001 from the National Hospital Discharge Survey (NHDS). Weekly influenza isolates by type and subtype were obtained from the WHO collaborating laboratories for the 1976 – 1977 through 1999 – 2000 seasons. Our models estimated annual averages of 6796 underlying pneumonia and influenza deaths and 28,076 underlying respiratory and circulatory deaths. The models estimated annual averages of 88,479 primary pneumonia and influenza hospitalizations and 225,985 primary respiratory and circulatory hospitalizations. We found significant increases in the numbers of influenza-associated deaths and hospitalizations by year among persons aged z65 years due to the aging of the population, the predominance of A(H3N2) viruses during the late 1990s and the increasing length of the influenza season during the 1990s. D 2004 Elsevier B.V. All rights reserved. Keywords: Influenza hospitalizations; Deaths models
1. Introduction In the United States, the Centers for Disease Control and Prevention (CDC) is responsible for providing national annual estimates of the burden of disease for influenza [1– 5]. Monitoring deaths and hospitalizations associated with influenza is important for planning annual resource needs associated with influenza epidemics and for determining costs and benefits associated with alternative influenza prevention and control strategies [6 –8]. Three influenza pandemics occurred during the 2000 century: the 1918 – 1920 A(H1N1) pandemic, the 1957 – 1960 A(H2N2) pandemic, and the 1968 –1972 A(H3N2) pandemic. These three influenza pandemics were associated with annual U.S. all-cause deaths of 225,000; 38,567 and 27,982, respectively, and deaths rates of 218, 22, and 14 deaths per 100,000 person-years, respectively [9]. The CDC estimates that influenza * Corresponding author. Tel.: +1-404-639-8896; fax: +1-404-639-8834. E-mail address: [email protected] (W.W. Thompson). 0531-5131/ D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.02.072
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viruses currently are associated with 36,000 respiratory and circulatory deaths annually [5]. Thus, annual deaths associated with influenza viruses in the United States actually exceed the numbers of annual deaths associated with the A(H3N2) pandemic, due in large part to the aging of the population [5]. Three methods have been used by CDC to estimate influenza-associated deaths and hospitalizations: rate-difference models [10 – 12], linear regression models, which do not incorporate viral data [2,3,13,14] and Poisson regression models, which incorporate viral data [5,15]. In this paper, we use Poisson regression models to provide updates of the estimates of annual numbers and rates of influenza-associated deaths and hospitalizations in the United States by age group. 2. Materials and methods Weekly influenza isolates by type and subtype were obtained from WHO collaborating laboratories for the 1976 –1977 through 1999 –2001 seasons. Mortality data were obtained from the NCHS and hospital data from the NHDS. Pneumonia and influenza hospitalizations and deaths were modeled by using ICD-9 codes, 480 –487, and ICD-10 codes, J10-J18. Respiratory and circulatory hospitalizations and deaths were modeled by using ICD-9 codes, 390 –519, and ICD-10 codes, I00 –I99 and J00 – J99. The CDC mortality model uses weekly mortality data and applies an age-specific Poisson regression model, Yij=a exp(b0+b1 [t]+b2 [t2]+b3 [sin(2pt/52)]+b4 [cos(2pt/ 52)]+b5 [A(H1N1)]+b6 [A(H3N2)]+b7 [B]), where Yij is the number of weekly deaths for outcome i in age group j, b0 is the intercept, b1 is a linear time trend, b2 is a quadratic time trend, b3 and b4 are cyclical changes in deaths, and b5 – b7 are the national percentages of specimens testing positive for influenza types/subtypes each week. The CDC hospitalization model uses a similar Poisson regression model, but uses monthly data for hospitalizations and viral terms. 3. Results 3.1. Annual estimates of influenza-associated deaths and hospitalizations in the United States From the 1976 –1977 through the 1999 –2000 respiratory seasons, we estimated that an annual average of 6796 (range 927– 14,556) pneumonia and influenza deaths and 28,076 (range 4348 – 53,616) respiratory and circulatory deaths were associated with the circulation of influenza viruses (Table 1). From the 1979 – 1980 through the 2000 –2001 respiratory seasons, we estimated that an annual average of 88,479 (range 19,666 – 208,173) pneumonia and influenza and 225,985 (range 65,300 –456,480) respiratory and circulatory hospitalizations were associated with influenza viruses. 3.2. Annual age-specific estimates of rates of influenza-associated deaths and hospitalizations in the United States In the United States, 2.5 underlying pneumonia and influenza deaths per 100,000 persons were associated with influenza viruses during the 1976 –1977 and 1999– 2000 respiratory seasons, while 10.7 underlying respiratory and circulatory deaths per 100,000
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W.W. Thompson et al. / International Congress Series 1263 (2004) 316–320
Table 1 Annual influenza-associated deaths and hospitalizations in the US Season
Influenza-associated deaths
Influenza-associated hospitalizations
Underlying P&I
Underlying R&C
Primary P&I
Primary R&C
1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Average
2073 4304 927 2016 3939 1092 5528 3059 8450 4218 1176 5124 4624 8079 3967 9169 6751 9527 7511 6275 13,271 14,556 14,426 9949 NA 6796
12,955 26,527 4348 10,265 22,228 5358 29,064 13,739 40,651 18,901 4444 23,506 18,054 34,944 16,168 37,582 27,228 37,977 30,046 25,010 50,039 53,616 52,273 38,513 NA 28,076
NA NA NA 47,022 35,356 22,353 55,934 56,878 86,332 65,695 19,666 57,387 82,494 79,035 93,902 80,848 119,678 89,734 99,574 99,932 148,418 167,599 208,173 142,635 87,889 88,479
NA NA NA 134,670 146,069 65,300 203,506 161,452 287,926 160,359 68,022 168,165 195,593 224,917 206,154 224,280 261,283 234,698 237,987 243,432 336,377 404,970 456,480 367,136 182,881 225,985
persons were associated with influenza (Table 2). In each category, rates of influenzaassociated deaths increased exponentially with increasing age. Persons agedz85 years were 32 times more likely to die from pneumonia and influenza compared with persons 65– 69 years, while those agedz85 years were 19 times more likely to experience a respiratory and circulatory death compared with those aged 65– 69 years. Approximately 35 pneumonia and influenza hospitalizations per 100,000 persons were associated with influenza viruses during the 1979 –1980 and 2000 – 2001 respiratory Table 2
Age-specific influenza-associated deaths and hospitalization rates Age group (years)
0–4 5 – 49 50 – 64 65 – 69 70 – 74 75 – 79 80 – 84 85+ Total a
Influenza-associated deaths ratesa
Influenza-associated hospitalization ratesa
Underlying P&I
Underlying R&C
Primary P&I
Primary R&C
0.2 0.2 1.1 3.0 5.9 12.2 29.7 97.9 2.5
0.5 0.3 6.2 18.6 32.8 64.7 127.4 351.4 10.7
14 5 35 56 134 213 307 652 35
118 21 88 168 365 464 679 1257 90
Rates per 100,00 person years.
W.W. Thompson et al. / International Congress Series 1263 (2004) 316–320
319
Fig. 1. Age-specific relative ratios of hospitalization rates to death rates.
seasons; 90 respiratory and circulatory hospitalizations per 100,000 persons were associated with influenza. Persons aged z85 years were 12 times more likely to be hospitalized with pneumonia and influenza compared with those 65– 69 years, and persons aged z85 years were seven times more likely to be hospitalized with a respiratory and circulatory condition compared with persons 65– 69 years. Children <5 years were at much greater risk for an influenza-associated hospitalization compared with an influenza-associated death (Fig. 1). In contrast, persons aged z85 years were almost as likely to die an influenza-associated death as they were to be hospitalized with an influenza-associated condition. 4. Discussion We estimated annual numbers and rates of influenza-associated deaths and hospitalizations in the United States by using more specific age groups than have previous studies. We demonstrated that both influenza-associated deaths and hospitalizations among persons aged z65 years have increased substantially in the US, likely due to the aging of the population, the predominance of A(H3N2) viruses during the late 1990s, and the increasing length of influenza seasons during the 1990s. Most influenza-associated hospitalizations and deaths occur among the elderly, and vaccinating the elderly will continue to be the primary strategy for preventing influenza-associated deaths and hospitalizations in this group [8]. Many studies [7,16] comparing outcomes in vaccinated with unvaccinated groups have shown that the currently available trivalent, inactivated influenza vaccine is effective in preventing both deaths and hospitalizations associated with influenza infections. Given the increasing numbers of influenza-associated hospitalizations and deaths among the elderly, several immunization strategies are currently being assessed to determine whether they may be more cost effective [17,18].
320
W.W. Thompson et al. / International Congress Series 1263 (2004) 316–320
References [1] T.C. Eickhoff, I.L. Sherman, R.E. Serfling, Observations on excess mortality associated with epidemic influenza, JAMA 176 (1961) 776 – 782. [2] R.E. Serfling, Methods for current statistical analysis of excess pneumonia-influenza deaths, Public Health Rep. 78 (6) (1963) 494 – 505. [3] K.J. Lui, A.P. Kendal, Impact of influenza epidemics on mortality in the United States from October 1972 to May 1985, Am. J. Public Health 77 (6) (1987) 712 – 716. [4] L. Simonsen, et al., The impact of influenza epidemics on hospitalizations, J. Infect. Dis. 181 (3) (2000) 831 – 837. [5] W.W. Thompson, et al., Mortality associated with influenza and respiratory syncytial virus in the United States, JAMA 289 (2) (2003) 179 – 186. [6] M.I. Meltzer, N.J. Cox, K. Fukuda, The economic impact of pandemic influenza in the United States: priorities for intervention, Emerg. Infect. Dis. 5 (5) (1999) 659 – 671. [7] K.L. Nichol, The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines, Vaccine 21 (16) (2003) 1769 – 1775. [8] C.B. Bridges, et al., Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm. Rep. 52 (RR-8) (2003) 1 – 34. [9] W.P. Glezen, Emerging infections: pandemic influenza, Epidemiol. Rev. 18 (1) (1996) 64 – 76. [10] W.H. Barker, J.P. Mullooly, Impact of epidemic type A influenza in a defined adult population, Am. J. Epidemiol. 112 (6) (1980) 798 – 811. [11] W.H. Barker, J.P. Mullooly, Pneumonia and influenza deaths during epidemics: implications for prevention, Arch. Intern. Med. 142 (1) (1982) 85 – 89. [12] H.S. Izurieta, et al., Influenza and the rates of hospitalization for respiratory disease among infants and young children, N. Engl. J. Med. 342 (4) (2000) 232 – 239. [13] K. Choi, S.B. Thacker, An evaluation of influenza mortality surveillance, 1962 – 1979: I. Time series forecasts of expected pneumonia and influenza deaths, Am. J. Epidemiol. 113 (3) (1981) 215 – 226. [14] L. Simonsen, et al., The impact of influenza epidemics on mortality: introducing a severity index, Am. J. Public Health 87 (12) (1997) 1944 – 1950. [15] K.M. Neuzil, et al., Winter respiratory viruses and health care use: a population-based study in the northwest United States, Clin. Infect. Dis. 37 (2) (2003) 201 – 207. [16] P.A. Gross, et al., The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature, Ann. Intern. Med. 123 (7) (1995) 518 – 527. [17] T.A. Reichert, et al., The Japanese experience with vaccinating schoolchildren against influenza, N. Engl. J. Med. 344 (12) (2001) 889 – 896. [18] I.M. Longini, et al., Estimation of the efficacy of live, attenuated influenza vaccine from a two-year, multicenter vaccine trial: implications for influenza epidemic control, Vaccine 18 (18) (2000) 1902 – 1909.