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Epidemiology of influenza
Vaccine 26S (2008) D45–D48
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Vaccine journal homepage: www.elsevier.com/locate/vaccine
Epidemiology of influenza Arnold S. Monto Department of Epidemiology, University of Michigan School of Public Health, 109 Observatory Street, Ann Arbor, MI 48109, United States
a r t i c l e
i n f o
Article history: Received 7 May 2008 Accepted 28 July 2008 Keywords: Influenza Epidemiology of influenza Influenza morbidity Influenza mortality Influenza control
a b s t r a c t The impact of influenza has been recognized for centuries. Its seasonality in temperate climates has allowed estimates of mortality and severe morbidity, such as hospitalization, to be made statistically, without identifying cases virologically. Most influenza related mortality occurs in older individuals and those with underlying conditions. In addition to those groups, influenza hospitalizations occur in younger children and pregnant women. Morbidity is more difficult to identify and laboratory confirmation is required for precise estimates to be made. Younger individuals experience the highest frequency of illnesses caused by all subtypes. This has resulted in suggested strategies for community control by vaccinating children. © 2008 Elsevier Ltd. All rights reserved.
Recognition of the occurrence of influenza and its overall impact can be traced back for centuries. It is difficult to know whether these events, identified from historic records because of production of greatly elevated morbidity or mortality, represent pandemics or what is currently termed seasonal influenza. Indeed, it is often not clear whether they were truly caused by influenza viruses [1,2]. This changed toward the end of the 19th century. Both pandemic and seasonal influenza were evaluated by those working with available public records, and the concepts that certain portions of the population were at particular risk began to be recognized [3]. Methods were developed which are still used today, such as use of mortality caused by pneumonia or influenza (P & I) as a specific gauge of the effect of outbreaks on deaths [4,5]. These methods allowed determination of the effect of the 1918 pandemic on mortality; the data in large part have stood the test of time [6,7]. This allowed recognition of the high case fatality in young adults as being distinct from the usual pattern associated with seasonal influenza. The unusual characteristics of 1918 later were confirmed when the 1957 and 1968 pandemic mortality pattern was found to more closely resemble what was expected with seasonal influenza [8,9]. The special situation of pandemics, when much of the population is totally susceptible to infection, is covered in another chapter. High attack rates in the 1957 pandemic allowed the distinction between influenza morbidity and mortality to be made. With some modifications, such as the mortality observed in young children, these observations apply to seasonal influenza as well. As shown in
E-mail address: [email protected]. 0264-410X/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2008.07.066
Fig. 1, data were obtained from two sources [10]. Mortality results were obtained from the entire country, but illness data came from one community [11,12]. In both situations, virology was not carried out to identify individual cases. Mortality was concentrated at the extremes of age, but mainly above age 64 years. This supported the practice of prioritizing vaccination to prevent mortality in the elderly. In contrast, morbidity mainly occurred in younger people; recognition of cases for inclusion was based on a case definition. This led to an artifact, the apparent sparing of young children who did not exhibit typical symptoms, but who are now known to experience frequent infection. As the behavior of influenza viruses in populations is examined, it is important to recognize whether cases are identified by virus identification or serology, or, as is most commonly the case, by epidemiologic means as was the case in Fig. 1.
1. Seasonality of influenza The fact that, in the temperate zone, influenza is highly seasonal is a major reason that it has been possible to estimate the impact of influenza without identifying those infected using laboratory techniques. In the Northern Hemisphere, there may be viruses identified at other times of the year, but outbreaks rarely begin before late November. Generally, outbreaks dominated by A (H3N2) start earlier, with type B following and often closing the season [13,14]. Especially in those years in which vaccine is late in arriving, it is helpful to continue vaccinations into early winter [15]. In many years, this approach will work. However, it needs to be recognized that sometimes, it will be too late to catch the peak of viral transmission. Typical outbreaks usually move through a community in
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A.S. Monto / Vaccine 26S (2008) D45–D48
Fig. 1. Clinical influenza attack rates (Kansas City, 1957) and annual mortality rate pneumonia and influenza (U.S., 1957).
12 weeks or more, but recent experience has reconfirmed that there is no such thing as a typical year. For example, in parts of the United States, in 2003, A/Fujian/411/02 (H3N2) began to produce major increases in illnesses, especially involving young children, in October [16]. This meant that outbreaks were taking place as the vaccination season was at its peak, fortunately a rare occurrence. In other areas of the world, especially those without a clear winter season, transmission patterns are different. The extreme is in regions such as Singapore, on the equator, where viruses have been isolated year round [17]. However, even there, and in much of the tropics, there are still peaks in transmission. Some areas have reported two such periods per year, with as would be expected, some variations from year to year [18]. One constant is the association of transmission with the rainy season [19]. Interestingly, this repeated observation is not in agreement with some experimental animal studies, which show that transmission increases in a dry environment [20]. It may be that factors, other than climatic conditions are involved, including social patterns, such as school holidays. This different seasonality of influenza periodicity in the tropics has made it more difficult to access impact [21]. Indeed, until recently, when it became possible to conduct virologic studies in these areas, it was assumed that influenza was a disease of colder climates, even though there was solid evidence to the contrary. Now, studies have begun, with virologic support, mainly in urban areas, which suggest that impact is at least as great in temperate regions, albeit with more diffuse occurrence [18,21]. These conclusions have obvious implications in terms of use of vaccines in a highly populated part of the world where vaccine has not been used much up to the present.
for type A (H3N2) viruses, perhaps because of more rapid drift of the latter. Therefore, older individuals are more likely to be infected by A (H3N2) than by other influenza viruses, just the viruses are the ones most likely to produce complications. With the availability of antivirals, the ability to identify cases of influenza based on clinical symptoms became important. For this purpose, the overall similarity of uncomplicated influenza caused by type A and B viruses allowed a unified analysis of those signs and symptoms which predicted that a respiratory illness was in fact caused by influenza virus. The issue had been examined before, using specimens obtained during surveillance [24]. Characteristics associated with influenza were similar to those previously reported, although some studies detected somewhat unexpected findings, such as the finding that conjunctivitis was significantly associated with influenza while sore throat was not [25]. A consistent finding was that the positive predictive value (PPV) of any symptom, that is, the likelihood that a case with a particular symptom or combination of symptoms would actually be influenza virologically was low, in the range of 40% [24]. However, recent studies have found that the PPV of certain symptoms, particularly cough and fever combined was as high as 87% [26,27]. What made the difference? The positive predictive value is affected by prevalence. This means that fever and cough are good predictors of the fact that a respiratory illness is actually influenza but only when it is known from surveillance data that influenza is actually circulating. The predictive value of these systems is affected by age [28]. It is useful in most adults and older children but not necessarily in the very young.
2. Effect of influenza type and subtype and of age
The historic observations that, in influenza outbreaks, certain population groups were at increased risk of death were made at a time when the influenza virus had not been identified. Even when influenza viruses could be isolated, identification of the viral etiology of an event as rare as death was not feasible, especially with the techniques then available. Several epidemiologic methods have been developed to estimate the number of deaths associated with influenza, using laboratory data as a driver in the analysis. The term “excess mortality” has been used to indicate that deaths from influenza occur above a baseline level of illnesses of the same type but not caused by influenza [29]. Traditionally, the cause of death so examined was pneumonia and influenza (P & I), based on a series of International Classification of Disease (ICD) codes. That outcome is still used in the United States for a rapid determination of severity of an influenza outbreak from 122 cities. It is known to be specific, but has been demonstrated in the past to miss many influenza-
The two type A viruses (H3N2) and (H1N1) and type B viruses produce illnesses of relatively similar clinical characteristics. However, in older children and healthy adults, it is possible to demonstrate that A (H3N2) virus is associated with the most severe illnesses, A (H1N1) the mildest, and type B intermediate. This can be observed in differences in overall duration of uncomplicated illnesses in the general population [12]. In the elderly and in other at-risk populations, complications leading to death or hospitalizations are generally associated with A (H3N2) [22]. Type B viruses are known to produce specific unusual conditions such as myositis, sometimes in clusters [23]. Infection frequency with the types and subtypes is related to age [14]. Children have the highest attack rates of all. However, frequency of infection falls more rapidly with increasing age for A (H1N1) and type B viruses than
3. Influenza impact: mortality and hospitalizations
A.S. Monto / Vaccine 26S (2008) D45–D48
related illnesses. Some years ago, it was recognized that heart, circulatory and nervous deaths also increased when influenza was being transmitted [30]. Therefore, when newer analytic approaches were introduced, they used, as an indicator of influenza, in addition to P & I, all cardiopulmonary deaths as well as all-cause mortality [31]. All-cause mortality was found to be too unstable, with very broad confidence intervals so that now influenza deaths are usually estimated on the basis of cardiopulmonary mortality [32]. Such analyses produced the estimate that, in the United States, 36,000 persons died on average annually from influenza. Most of these deaths were in individuals over age 65 years; the age group with the next highest mortality rates were those 50–64 years of age, many of whom are know to have underlying conditions. The data have confirmed the priority assigned in most developed countries for vaccination of persons above age 59 or 64 years. In the United States, based on these findings, those 50 years of age and above are recommended to be vaccinated. Other population groups, while not experiencing detectible mortality in influenza outbreaks do have clear associated hospitalization, as evidence of severe outcomes. In the 1918 and to a lesser extent in the 1957 pandemic, pregnant women experienced elevated morbidity, with spontaneous abortions in those who survived [33]. In seasonal influenza, such mortality is not detectable. However, it was always recognized that pregnant women with underlying conditions were at particular risk, and they were covered by vaccination recommendations. More recently, studies carried out using governmental data bases over a period of 19 years confirmed that there was risk of hospitalization for cardiopulmonary outcomes which increased as pregnancy proceeded among those without underlying conditions [34]. It was also clear was that the risk of hospitalization was still approximately five-fold higher for those with underlying conditions than those without. On the basis of these results, some countries have recommended vaccination for all pregnant women. This approach may bring the added benefit of protecting the newborn children. While excess mortality among young children has been consistently observed in pandemics, it is not a feature of seasonal influenza. Deaths do occur and have been documented, especially in years where there are high attack rates. These deaths produce a public reaction when they are clustered in a particular region and occur over a short period of time. In contrast to deaths, at least in developed countries, hospitalizations are associated with influenza in children [35–37]. Data have been collected from a number of countries, including the Hong Kong Special Administrative region of China. All confirm, using both statistical methods, and in some cases identification of illness etiology virologically, that younger children are at elevated risk of influenza hospitalization. This applies particularly to those under 2 years of age, but the highest frequency is in children under age 6 months. As a result of these findings, studies conducted in children without recognized risk conditions, vaccination has been recommended in some countries for young children. Since children under age 6 months cannot be given current vaccines, their families have also been recommended for vaccination to indirectly protect those infants. 4. Influenza morbidity and indirect protection It is much more difficult to quantify influenza morbidity. While it is possible to identify typical influenza based on clinical characteristics during the influenza season, much influenza is milder and would not be recognized without laboratory confirmation. Such studies, which have been done in large enough populations and over several seasons, characteristics which allow generalizability have been found [38]. A generalization, based on a limited number of studies conducted long enough, is that infection rates may
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be as high as 40% in young children and, if half of these infections are symptomatic, this would translate into a clinical attack rate of 20% [14]. In other years, the attack rate may be half that. In recent clinical trials involving young adults, the clinical attack rates have been in the range of 5% or less in unvaccinated individuals [39]. Whatever the source of data, children have been found to have by far the highest infection rates. While vaccination of school-age children cannot be advocated for reduction in mortality or even in hospitalization, there is a case for preventing the high morbidity frequently observed in this large population group [40]. Additionally, as indicated in mathematical models, vaccinating school-age children should reduce overall transmission within the community, thus producing indirect protection for the rest [41]. These results, based on assumptions concerning the amount of transmission taking place in the school as opposed to the rest of the community, are also the basis for recommending school closure during a pandemic. Studying the affect of school child vaccination experimentally is difficult for a number of reasons. The entire community rather that the individual becomes the unit of observation. Conclusions cannot be as firm as those resulting from randomized controlled trials. The initial experimental study to examine this question was carried out during the A (H3N2) pandemic [42]. Vaccination of 85% of the school-age children in Tecumseh, MI, USA, led to an overall reduction in transmission in all age groups. Another study conducted in Novgorod, Russia, found that teachers in classrooms in which students were vaccinated as well as unvaccinated students in those classrooms were protected [43]. More recent studies have confirmed the value of school child vaccination to reduce community transmission although precise estimates vary [44,45]. A concern with any strategy involving vaccinating so many annually is the ability to sustain programs. Development of new vaccines which may not need to be given each year will help with implementation of such a plan. References [1] Langmuir AD, Worthen TD, Solomon J, Ray CG, Petersen E. The Thucydides syndrome: a new hypothesis for the cause of the plague of Athens. N Engl J Med 1985;313:1027–30. [2] Francis Jr T. Influenza: the new acquaintance. Ann Intern Med 1953;39:203–21. [3] Farr W. Vital statistics. London: Office of the Sanitary Institute; 1885. p. 330. [4] Pearl R. Influenza studies. I. On certain general statistical aspects of the 1918 epidemic in American cities. Public Health Rep 1919;34:1743–83. [5] Craig JD, Dublin LI. The influenza epidemic of 1918. Trans Actuarial Soc Am 1920;61:134. [6] Luk J, Gross P, Thompson WW. Observations on mortality during the 1918 influenza pandemic. Clin Infect Dis 2001;33:1375–8. [7] Nguyen-Van-Tam JS, Hampson AW. The epidemiology and clinical impact of pandemic influenza. Vaccine 2003;21:1762–8. [8] Dunn FL. Pandemic influenza in 1957. Am J Med Assoc 1958;166:1140–8. [9] Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998;178:53–60. [10] Monto AS. Influenza: quantifying morbidity and mortality. Am J Med 1967;82(s6A):20–5. [11] Serfling RE, Sherman IL, Housworth WJ. Excess pneumonia–influenza mortality by age and sex in three major influenza A 2 epidemics, United States, 1957–1958, 1960 and 1963. Am J Epidemiol 1967;86:433–41. [12] Chin TDY, Foley JF, Doto IL, Gravelle CR, Weston J. Morbidity and mortality characteristics of Asian strain influenza. Public Health Rep 1960;75:149–58. [13] Monto AS, Kioumehr F. The Tecumseh study of respiratory illness. IX. Occurrence of influenza in the community, 1966–1971. Am J Epidemiol 1975;102:553–63. [14] Monto AS, Koopman JS, Longini IM. Tecumseh study of illness. XIII. Influenza infection and disease 1976–1981. Am J Epidemiol 1985;121:811–22. [15] http://www.cdc.gov/flu/profesisionals/acip/timng.htm, accessed on April 24; 2008. [16] Bhat N, Wright JG, Broder KR, Murray EL, Greenberg ME, Glover MJ, et al. Influenza-associated deaths among children in the United States 2003–2004. N Engl J Med 2005;353:2559–67. [17] Ng TP, Pwee KH, Niti M, Goh LG. Influenza in Singapore: assessing the burden of illness in the community. Ann Acad Med Singapore 2002;31:182–8.
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[18] Chiu SS, Lau YL, Chan KH, Wong WHS, Malik Peiris JS. Influenza-related hospitalizations among children in Hong Kong. N Engl J Med 2002;347: 2097–103. [19] Monto AS, Johnson KM. A community study of respiratory infections in the tropics. I. Description of the community and observations on the activity of certain respiratory agents. Am J Epidemiol 1967;86:77–92. [20] Lowen AC, Mubareka S, Tumpey TM, Garcia-Sastre A, Palese P. The guinea pig as a transmission model for human influenza viruses. PNAS 2006;103: 9988–92. [21] Simmerman JM, Thawatsupha P, Kingnate D, Fukuda K, Chaising A, Dowell S. Influenza in Thailand: a case study for middle income countries. Vaccine 2004;23:182–7. [22] Lui KJ, Kendal AP. Impact of influenza epidemics on mortality in the United States from October 1973 to May 1985. Am J Public Health 1987;77:712–6. [23] Baine WB, Luby JP, Martin SM. Severe illness with influenza B. Am J Med 1980;68:181–9. [24] Carrat F, Tachet A, Rouzioux C, Housset B, Valleron AJ. Evaluations of clinical case definitions of influenza: detailed investigation of patients during the 1995–1996 epidemic in France. Clin Infect Dis 1999;28:283–90. [25] Monto AS, Ohmit SE. The evolving epidemiology of influenza infection and disease. In: Brown LE, Hampson AW, Webster RG, editors. Options for control of influenza, vol. III. Amsterdam, The Netherlands: Elsevier Science BV; 1996. p. 45–9. [26] Monto AS, Gravenstein S, Elliot M, Colopy M, Schweinle J. Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000;160:3242–7. [27] Boivin G, Hardy I, Tellier G, Maziade J. Predicting influenza infections during epidemics with use of a clinical case definition. Clin Infect Dis 2000;31:1166–9. [28] Ohmit SE, Monto AS. Symptomatic predictors of influenza virus positivity in children during the influenza season. Clin Infect Dis 2006;43:564–8. [29] Serfling RE. Methods for current statistical analysis of excess pneumonia– influenza deaths. Public Health Rep 1963;78:494–506. [30] Housworth J, Langmuir AD. Excess mortality from epidemic influenza 1957–1966. Am J Epidemiol 1974;100:40–8. [31] Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, Schonberger LB. The impact of influenza epidemics on mortality: introducing a severity index. Am J Public Health 1997;87:1944–50. [32] Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. J Am Med Assoc 2003;289:179–86.
[33] Harris JW. Influenza occurring in pregnant women: a statistical study of thirteen hundred and fifty cases. J Am Med Assoc 1919;72:978–80. [34] Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998;148:1094–102. [35] Neuzil KM, Mellen BG, Wright PF, Mitchel EF, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225–31. [36] Izurieta HS, Thompson WW, Kramarz P, Shay DK, Davis RL, DeStefano F, et al. Influenza and the rates of hospitalizations for respiratory disease among infants and young children. N Engl J Med 2000;342:332–9. [37] Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, et al. Influenza-associated hospitalizations in the United States. J Am Med Assoc 2004;292:1333–40. [38] Sullivan KM, Monto AS, Longini IM. Estimates of the US health impact of influenza. Am J Public Health 1993;83:1712–6. [39] Ohmit SE, Victor JC, Rotthoff JR, Teich ER, Truscon RK, Baum LL, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med 2006;355:2513–22. [40] Heikkinen T, Silvennoinen H, Peltola V, Ziegler T, Vainionpaa R, Vuorinen T, et al. Burden of influenza in children in the community. J Infect Dis 2004;190:1369–73. [41] Weycker D, Edelsberg J, Halloran ME, Longini IM, Nizam A, Ciuryla V, et al. Population-wide benefits of routine vaccination of children against influenza. Vaccine 2005;23:1284–93. [42] Monto AS, Davenport FM, Napier JA, Francis T. Modifications of an outbreak of influenza in Tecumseh Michigan by vaccination of schoolchildren. J Infect Dis 1970;122:16–25. [43] Rudenko LG, Slepushkin AN, Monto AS, Kendal AP, Grigorieva EP, Burtseva EP, et al. Efficacy of live attenuated and inactivated influenza vaccines in schoolchildren and their unvaccinated contacts in Novgorod Russia. J Infect Dis 1993;168:881–7. [44] Piedra PA, Gaglani MJ, Kozinetz CA, Herschler G, Riggs M, Griffith M, et al. Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Vaccine 2005;23:1540–8. [45] King JC, Stoddard JJ, Gaglani MJ, Moore KA, Magder L, McClure E, et al. Effectiveness of school-based influenza vaccination. N Engl J Med 2006;355: 2523–32.
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Epidemiology of influenza Arnold S. Monto Department of Epidemiology, University of Michigan School of Public Health, 109 Observatory Street, Ann Arbor, MI 48109, United States
a r t i c l e
i n f o
Article history: Received 7 May 2008 Accepted 28 July 2008 Keywords: Influenza Epidemiology of influenza Influenza morbidity Influenza mortality Influenza control
a b s t r a c t The impact of influenza has been recognized for centuries. Its seasonality in temperate climates has allowed estimates of mortality and severe morbidity, such as hospitalization, to be made statistically, without identifying cases virologically. Most influenza related mortality occurs in older individuals and those with underlying conditions. In addition to those groups, influenza hospitalizations occur in younger children and pregnant women. Morbidity is more difficult to identify and laboratory confirmation is required for precise estimates to be made. Younger individuals experience the highest frequency of illnesses caused by all subtypes. This has resulted in suggested strategies for community control by vaccinating children. © 2008 Elsevier Ltd. All rights reserved.
Recognition of the occurrence of influenza and its overall impact can be traced back for centuries. It is difficult to know whether these events, identified from historic records because of production of greatly elevated morbidity or mortality, represent pandemics or what is currently termed seasonal influenza. Indeed, it is often not clear whether they were truly caused by influenza viruses [1,2]. This changed toward the end of the 19th century. Both pandemic and seasonal influenza were evaluated by those working with available public records, and the concepts that certain portions of the population were at particular risk began to be recognized [3]. Methods were developed which are still used today, such as use of mortality caused by pneumonia or influenza (P & I) as a specific gauge of the effect of outbreaks on deaths [4,5]. These methods allowed determination of the effect of the 1918 pandemic on mortality; the data in large part have stood the test of time [6,7]. This allowed recognition of the high case fatality in young adults as being distinct from the usual pattern associated with seasonal influenza. The unusual characteristics of 1918 later were confirmed when the 1957 and 1968 pandemic mortality pattern was found to more closely resemble what was expected with seasonal influenza [8,9]. The special situation of pandemics, when much of the population is totally susceptible to infection, is covered in another chapter. High attack rates in the 1957 pandemic allowed the distinction between influenza morbidity and mortality to be made. With some modifications, such as the mortality observed in young children, these observations apply to seasonal influenza as well. As shown in
E-mail address: [email protected]. 0264-410X/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2008.07.066
Fig. 1, data were obtained from two sources [10]. Mortality results were obtained from the entire country, but illness data came from one community [11,12]. In both situations, virology was not carried out to identify individual cases. Mortality was concentrated at the extremes of age, but mainly above age 64 years. This supported the practice of prioritizing vaccination to prevent mortality in the elderly. In contrast, morbidity mainly occurred in younger people; recognition of cases for inclusion was based on a case definition. This led to an artifact, the apparent sparing of young children who did not exhibit typical symptoms, but who are now known to experience frequent infection. As the behavior of influenza viruses in populations is examined, it is important to recognize whether cases are identified by virus identification or serology, or, as is most commonly the case, by epidemiologic means as was the case in Fig. 1.
1. Seasonality of influenza The fact that, in the temperate zone, influenza is highly seasonal is a major reason that it has been possible to estimate the impact of influenza without identifying those infected using laboratory techniques. In the Northern Hemisphere, there may be viruses identified at other times of the year, but outbreaks rarely begin before late November. Generally, outbreaks dominated by A (H3N2) start earlier, with type B following and often closing the season [13,14]. Especially in those years in which vaccine is late in arriving, it is helpful to continue vaccinations into early winter [15]. In many years, this approach will work. However, it needs to be recognized that sometimes, it will be too late to catch the peak of viral transmission. Typical outbreaks usually move through a community in
D46
A.S. Monto / Vaccine 26S (2008) D45–D48
Fig. 1. Clinical influenza attack rates (Kansas City, 1957) and annual mortality rate pneumonia and influenza (U.S., 1957).
12 weeks or more, but recent experience has reconfirmed that there is no such thing as a typical year. For example, in parts of the United States, in 2003, A/Fujian/411/02 (H3N2) began to produce major increases in illnesses, especially involving young children, in October [16]. This meant that outbreaks were taking place as the vaccination season was at its peak, fortunately a rare occurrence. In other areas of the world, especially those without a clear winter season, transmission patterns are different. The extreme is in regions such as Singapore, on the equator, where viruses have been isolated year round [17]. However, even there, and in much of the tropics, there are still peaks in transmission. Some areas have reported two such periods per year, with as would be expected, some variations from year to year [18]. One constant is the association of transmission with the rainy season [19]. Interestingly, this repeated observation is not in agreement with some experimental animal studies, which show that transmission increases in a dry environment [20]. It may be that factors, other than climatic conditions are involved, including social patterns, such as school holidays. This different seasonality of influenza periodicity in the tropics has made it more difficult to access impact [21]. Indeed, until recently, when it became possible to conduct virologic studies in these areas, it was assumed that influenza was a disease of colder climates, even though there was solid evidence to the contrary. Now, studies have begun, with virologic support, mainly in urban areas, which suggest that impact is at least as great in temperate regions, albeit with more diffuse occurrence [18,21]. These conclusions have obvious implications in terms of use of vaccines in a highly populated part of the world where vaccine has not been used much up to the present.
for type A (H3N2) viruses, perhaps because of more rapid drift of the latter. Therefore, older individuals are more likely to be infected by A (H3N2) than by other influenza viruses, just the viruses are the ones most likely to produce complications. With the availability of antivirals, the ability to identify cases of influenza based on clinical symptoms became important. For this purpose, the overall similarity of uncomplicated influenza caused by type A and B viruses allowed a unified analysis of those signs and symptoms which predicted that a respiratory illness was in fact caused by influenza virus. The issue had been examined before, using specimens obtained during surveillance [24]. Characteristics associated with influenza were similar to those previously reported, although some studies detected somewhat unexpected findings, such as the finding that conjunctivitis was significantly associated with influenza while sore throat was not [25]. A consistent finding was that the positive predictive value (PPV) of any symptom, that is, the likelihood that a case with a particular symptom or combination of symptoms would actually be influenza virologically was low, in the range of 40% [24]. However, recent studies have found that the PPV of certain symptoms, particularly cough and fever combined was as high as 87% [26,27]. What made the difference? The positive predictive value is affected by prevalence. This means that fever and cough are good predictors of the fact that a respiratory illness is actually influenza but only when it is known from surveillance data that influenza is actually circulating. The predictive value of these systems is affected by age [28]. It is useful in most adults and older children but not necessarily in the very young.
2. Effect of influenza type and subtype and of age
The historic observations that, in influenza outbreaks, certain population groups were at increased risk of death were made at a time when the influenza virus had not been identified. Even when influenza viruses could be isolated, identification of the viral etiology of an event as rare as death was not feasible, especially with the techniques then available. Several epidemiologic methods have been developed to estimate the number of deaths associated with influenza, using laboratory data as a driver in the analysis. The term “excess mortality” has been used to indicate that deaths from influenza occur above a baseline level of illnesses of the same type but not caused by influenza [29]. Traditionally, the cause of death so examined was pneumonia and influenza (P & I), based on a series of International Classification of Disease (ICD) codes. That outcome is still used in the United States for a rapid determination of severity of an influenza outbreak from 122 cities. It is known to be specific, but has been demonstrated in the past to miss many influenza-
The two type A viruses (H3N2) and (H1N1) and type B viruses produce illnesses of relatively similar clinical characteristics. However, in older children and healthy adults, it is possible to demonstrate that A (H3N2) virus is associated with the most severe illnesses, A (H1N1) the mildest, and type B intermediate. This can be observed in differences in overall duration of uncomplicated illnesses in the general population [12]. In the elderly and in other at-risk populations, complications leading to death or hospitalizations are generally associated with A (H3N2) [22]. Type B viruses are known to produce specific unusual conditions such as myositis, sometimes in clusters [23]. Infection frequency with the types and subtypes is related to age [14]. Children have the highest attack rates of all. However, frequency of infection falls more rapidly with increasing age for A (H1N1) and type B viruses than
3. Influenza impact: mortality and hospitalizations
A.S. Monto / Vaccine 26S (2008) D45–D48
related illnesses. Some years ago, it was recognized that heart, circulatory and nervous deaths also increased when influenza was being transmitted [30]. Therefore, when newer analytic approaches were introduced, they used, as an indicator of influenza, in addition to P & I, all cardiopulmonary deaths as well as all-cause mortality [31]. All-cause mortality was found to be too unstable, with very broad confidence intervals so that now influenza deaths are usually estimated on the basis of cardiopulmonary mortality [32]. Such analyses produced the estimate that, in the United States, 36,000 persons died on average annually from influenza. Most of these deaths were in individuals over age 65 years; the age group with the next highest mortality rates were those 50–64 years of age, many of whom are know to have underlying conditions. The data have confirmed the priority assigned in most developed countries for vaccination of persons above age 59 or 64 years. In the United States, based on these findings, those 50 years of age and above are recommended to be vaccinated. Other population groups, while not experiencing detectible mortality in influenza outbreaks do have clear associated hospitalization, as evidence of severe outcomes. In the 1918 and to a lesser extent in the 1957 pandemic, pregnant women experienced elevated morbidity, with spontaneous abortions in those who survived [33]. In seasonal influenza, such mortality is not detectable. However, it was always recognized that pregnant women with underlying conditions were at particular risk, and they were covered by vaccination recommendations. More recently, studies carried out using governmental data bases over a period of 19 years confirmed that there was risk of hospitalization for cardiopulmonary outcomes which increased as pregnancy proceeded among those without underlying conditions [34]. It was also clear was that the risk of hospitalization was still approximately five-fold higher for those with underlying conditions than those without. On the basis of these results, some countries have recommended vaccination for all pregnant women. This approach may bring the added benefit of protecting the newborn children. While excess mortality among young children has been consistently observed in pandemics, it is not a feature of seasonal influenza. Deaths do occur and have been documented, especially in years where there are high attack rates. These deaths produce a public reaction when they are clustered in a particular region and occur over a short period of time. In contrast to deaths, at least in developed countries, hospitalizations are associated with influenza in children [35–37]. Data have been collected from a number of countries, including the Hong Kong Special Administrative region of China. All confirm, using both statistical methods, and in some cases identification of illness etiology virologically, that younger children are at elevated risk of influenza hospitalization. This applies particularly to those under 2 years of age, but the highest frequency is in children under age 6 months. As a result of these findings, studies conducted in children without recognized risk conditions, vaccination has been recommended in some countries for young children. Since children under age 6 months cannot be given current vaccines, their families have also been recommended for vaccination to indirectly protect those infants. 4. Influenza morbidity and indirect protection It is much more difficult to quantify influenza morbidity. While it is possible to identify typical influenza based on clinical characteristics during the influenza season, much influenza is milder and would not be recognized without laboratory confirmation. Such studies, which have been done in large enough populations and over several seasons, characteristics which allow generalizability have been found [38]. A generalization, based on a limited number of studies conducted long enough, is that infection rates may
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be as high as 40% in young children and, if half of these infections are symptomatic, this would translate into a clinical attack rate of 20% [14]. In other years, the attack rate may be half that. In recent clinical trials involving young adults, the clinical attack rates have been in the range of 5% or less in unvaccinated individuals [39]. Whatever the source of data, children have been found to have by far the highest infection rates. While vaccination of school-age children cannot be advocated for reduction in mortality or even in hospitalization, there is a case for preventing the high morbidity frequently observed in this large population group [40]. Additionally, as indicated in mathematical models, vaccinating school-age children should reduce overall transmission within the community, thus producing indirect protection for the rest [41]. These results, based on assumptions concerning the amount of transmission taking place in the school as opposed to the rest of the community, are also the basis for recommending school closure during a pandemic. Studying the affect of school child vaccination experimentally is difficult for a number of reasons. The entire community rather that the individual becomes the unit of observation. Conclusions cannot be as firm as those resulting from randomized controlled trials. The initial experimental study to examine this question was carried out during the A (H3N2) pandemic [42]. Vaccination of 85% of the school-age children in Tecumseh, MI, USA, led to an overall reduction in transmission in all age groups. Another study conducted in Novgorod, Russia, found that teachers in classrooms in which students were vaccinated as well as unvaccinated students in those classrooms were protected [43]. More recent studies have confirmed the value of school child vaccination to reduce community transmission although precise estimates vary [44,45]. A concern with any strategy involving vaccinating so many annually is the ability to sustain programs. Development of new vaccines which may not need to be given each year will help with implementation of such a plan. References [1] Langmuir AD, Worthen TD, Solomon J, Ray CG, Petersen E. The Thucydides syndrome: a new hypothesis for the cause of the plague of Athens. N Engl J Med 1985;313:1027–30. [2] Francis Jr T. Influenza: the new acquaintance. Ann Intern Med 1953;39:203–21. [3] Farr W. Vital statistics. London: Office of the Sanitary Institute; 1885. p. 330. [4] Pearl R. Influenza studies. I. On certain general statistical aspects of the 1918 epidemic in American cities. Public Health Rep 1919;34:1743–83. [5] Craig JD, Dublin LI. The influenza epidemic of 1918. Trans Actuarial Soc Am 1920;61:134. [6] Luk J, Gross P, Thompson WW. Observations on mortality during the 1918 influenza pandemic. Clin Infect Dis 2001;33:1375–8. [7] Nguyen-Van-Tam JS, Hampson AW. The epidemiology and clinical impact of pandemic influenza. Vaccine 2003;21:1762–8. [8] Dunn FL. Pandemic influenza in 1957. Am J Med Assoc 1958;166:1140–8. [9] Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998;178:53–60. [10] Monto AS. Influenza: quantifying morbidity and mortality. Am J Med 1967;82(s6A):20–5. [11] Serfling RE, Sherman IL, Housworth WJ. Excess pneumonia–influenza mortality by age and sex in three major influenza A 2 epidemics, United States, 1957–1958, 1960 and 1963. Am J Epidemiol 1967;86:433–41. [12] Chin TDY, Foley JF, Doto IL, Gravelle CR, Weston J. Morbidity and mortality characteristics of Asian strain influenza. Public Health Rep 1960;75:149–58. [13] Monto AS, Kioumehr F. The Tecumseh study of respiratory illness. IX. Occurrence of influenza in the community, 1966–1971. Am J Epidemiol 1975;102:553–63. [14] Monto AS, Koopman JS, Longini IM. Tecumseh study of illness. XIII. Influenza infection and disease 1976–1981. Am J Epidemiol 1985;121:811–22. [15] http://www.cdc.gov/flu/profesisionals/acip/timng.htm, accessed on April 24; 2008. [16] Bhat N, Wright JG, Broder KR, Murray EL, Greenberg ME, Glover MJ, et al. Influenza-associated deaths among children in the United States 2003–2004. N Engl J Med 2005;353:2559–67. [17] Ng TP, Pwee KH, Niti M, Goh LG. Influenza in Singapore: assessing the burden of illness in the community. Ann Acad Med Singapore 2002;31:182–8.
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[18] Chiu SS, Lau YL, Chan KH, Wong WHS, Malik Peiris JS. Influenza-related hospitalizations among children in Hong Kong. N Engl J Med 2002;347: 2097–103. [19] Monto AS, Johnson KM. A community study of respiratory infections in the tropics. I. Description of the community and observations on the activity of certain respiratory agents. Am J Epidemiol 1967;86:77–92. [20] Lowen AC, Mubareka S, Tumpey TM, Garcia-Sastre A, Palese P. The guinea pig as a transmission model for human influenza viruses. PNAS 2006;103: 9988–92. [21] Simmerman JM, Thawatsupha P, Kingnate D, Fukuda K, Chaising A, Dowell S. Influenza in Thailand: a case study for middle income countries. Vaccine 2004;23:182–7. [22] Lui KJ, Kendal AP. Impact of influenza epidemics on mortality in the United States from October 1973 to May 1985. Am J Public Health 1987;77:712–6. [23] Baine WB, Luby JP, Martin SM. Severe illness with influenza B. Am J Med 1980;68:181–9. [24] Carrat F, Tachet A, Rouzioux C, Housset B, Valleron AJ. Evaluations of clinical case definitions of influenza: detailed investigation of patients during the 1995–1996 epidemic in France. Clin Infect Dis 1999;28:283–90. [25] Monto AS, Ohmit SE. The evolving epidemiology of influenza infection and disease. In: Brown LE, Hampson AW, Webster RG, editors. Options for control of influenza, vol. III. Amsterdam, The Netherlands: Elsevier Science BV; 1996. p. 45–9. [26] Monto AS, Gravenstein S, Elliot M, Colopy M, Schweinle J. Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000;160:3242–7. [27] Boivin G, Hardy I, Tellier G, Maziade J. Predicting influenza infections during epidemics with use of a clinical case definition. Clin Infect Dis 2000;31:1166–9. [28] Ohmit SE, Monto AS. Symptomatic predictors of influenza virus positivity in children during the influenza season. Clin Infect Dis 2006;43:564–8. [29] Serfling RE. Methods for current statistical analysis of excess pneumonia– influenza deaths. Public Health Rep 1963;78:494–506. [30] Housworth J, Langmuir AD. Excess mortality from epidemic influenza 1957–1966. Am J Epidemiol 1974;100:40–8. [31] Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, Schonberger LB. The impact of influenza epidemics on mortality: introducing a severity index. Am J Public Health 1997;87:1944–50. [32] Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. J Am Med Assoc 2003;289:179–86.
[33] Harris JW. Influenza occurring in pregnant women: a statistical study of thirteen hundred and fifty cases. J Am Med Assoc 1919;72:978–80. [34] Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998;148:1094–102. [35] Neuzil KM, Mellen BG, Wright PF, Mitchel EF, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225–31. [36] Izurieta HS, Thompson WW, Kramarz P, Shay DK, Davis RL, DeStefano F, et al. Influenza and the rates of hospitalizations for respiratory disease among infants and young children. N Engl J Med 2000;342:332–9. [37] Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, et al. Influenza-associated hospitalizations in the United States. J Am Med Assoc 2004;292:1333–40. [38] Sullivan KM, Monto AS, Longini IM. Estimates of the US health impact of influenza. Am J Public Health 1993;83:1712–6. [39] Ohmit SE, Victor JC, Rotthoff JR, Teich ER, Truscon RK, Baum LL, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med 2006;355:2513–22. [40] Heikkinen T, Silvennoinen H, Peltola V, Ziegler T, Vainionpaa R, Vuorinen T, et al. Burden of influenza in children in the community. J Infect Dis 2004;190:1369–73. [41] Weycker D, Edelsberg J, Halloran ME, Longini IM, Nizam A, Ciuryla V, et al. Population-wide benefits of routine vaccination of children against influenza. Vaccine 2005;23:1284–93. [42] Monto AS, Davenport FM, Napier JA, Francis T. Modifications of an outbreak of influenza in Tecumseh Michigan by vaccination of schoolchildren. J Infect Dis 1970;122:16–25. [43] Rudenko LG, Slepushkin AN, Monto AS, Kendal AP, Grigorieva EP, Burtseva EP, et al. Efficacy of live attenuated and inactivated influenza vaccines in schoolchildren and their unvaccinated contacts in Novgorod Russia. J Infect Dis 1993;168:881–7. [44] Piedra PA, Gaglani MJ, Kozinetz CA, Herschler G, Riggs M, Griffith M, et al. Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Vaccine 2005;23:1540–8. [45] King JC, Stoddard JJ, Gaglani MJ, Moore KA, Magder L, McClure E, et al. Effectiveness of school-based influenza vaccination. N Engl J Med 2006;355: 2523–32.