The Threat of Pandemic Influenza Are We Ready? Workshop Summary (2005) / Chapter Skim
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1 The Story of Influenza
1 The Story of Influenza
Pages 57-114
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From page 57... ...
Since then, mankind has gained several advantages against the disease: experience of three better characterized pandemics (1918, 1957, and 1968) ; knowledge of influenza viruses; capacity to design and manufacture vaccines and antiviral drugs to forestall (if not prevent)
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From page 58... ...
In a parallel effort, subsequently described, epidemiologists are analyzing death records and serological data to better understand patterns of transmission, morbidity, and mortality in past influenza pandemics. Such findings could inform planning for public health interventions to reduce the incidence of severe outcomes in future pandemics.
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From page 59... ...
The Virus Itself The pandemic in 1918 was hardly the first influenza pandemic, nor was it the only lethal one. Throughout history, there have been influenza pandemics, some of which may have rivaled 1918's lethality.
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. Within a few weeks of that Lancet article appearing, a second pandemic wave swept around the world.
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In 1918, pathologists were intimately familiar with the condition of lungs of victims of bacterial pneumonia at autopsy. But the viral pneumonias caused by the influenza pandemic were so violent that many investigators said the only lungs they had seen that resembled them were from victims of poison gas.
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ARDS mortality rates today range from 40 to 60 percent, even with support in modern intensive care units (ICUs)
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But in those same places, the people struck by influenza later in the epidemic were not becoming as ill, and were not dying at the same rate, as those struck in the first 2 to 3 weeks. Cities struck later in the epidemic also usually had lower mortality rates.
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From page 64... ...
Even in Army camps, where one could expect communication between physicians from one camp to the next, there seemed to be no improvements in medical care that could account for the different mortality rates. A distinguished investigator specifically looked for evidence of improved care or better preventive measures in Army camps and found none.
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From page 65... ...
In Chicago, the Cook County Hospital mortality rate of all influenza admissions -- not just those who developed pneumonia -- was 39.8 percent (Keeton and Cusman, 1918)
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In rural Kentucky, the Red Cross reported "people starving to death not from lack of food but because the well were panic stricken and would not go near the sick" (An Account of the Influenza Epidemic, 1919)
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From page 67... ...
They considered the most likely sites of origin to be France and the United States, and most agreed with Macfarlane Burnet, who concluded that the evidence was "strongly suggestive" that the 1918 influenza pandemic began in the United States, and that its spread was "intimately related to war conditions and especially the arrival of American troops in France" (Burnet and Clark, 1942)
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From page 68... ...
, 1918, 1957, and 1968 might tell us whether each followed the same patterns, which in turn could help us to devise strategies for the use of antivirals and vaccines. The Next Pandemic Virtually every expert on influenza believes another pandemic is nearly inevitable, that it will kill millions of people, and that it could kill tens of millions -- and a virus like 1918, or H5N1, might kill a hundred million or more -- and that it could cause economic and social disruption on a massive scale.
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From page 69... ...
They continually circulate in humans in yearly epidemics (mainly in the winter in temperate climates) and antigenically novel virus strains emerge sporadically as pandemic viruses (Cox and Subbarao, 2000)
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From page 70... ...
Human influenza virus strains with recently acquired avian surface and internal protein-encoding RNA segments were responsible for the pandemic influenza outbreaks in 1957 and 1968 (Scholtissek et al., 1978a; Kawaoka et al., 1989)
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. Prior to the analyses on the 1918 virus described in this review, only two pandemic influenza virus strains were available for molecular analysis: the H2N2 virus strain from 1957 and the H3N2 virus strain from 1968.
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Interpandemic influenza outbreaks generally occur in a single annual wave in the late winter. The severity of annual outbreaks is affected by antigenic drift, with an antigenically modified virus strain emerging every 2 to 3 years.
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. These findings are consistent with infection by a well-adapted influenza virus capable of rapid replication throughout the entire respiratory tree (Reid and Taubenberger, 1999; Taubenberger et al., 70 65 60 55 Age 50 45 40 35 1900 1906 1912 1918 1924 1930 1936 1942 1948 1954 1960 Date FIGURE 1-1 Life expectancy in the United States, 19001960, showing the impact of the 1918 influenza pandemic.
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From page 74... ...
. The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza mortality was higher in those younger than age 65 than in those older than 65.
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. Since 1918 there have been many examples of both H1N1 and H3N2 human influenza A virus strains becoming established in swine (Brown et al., 1998; Castrucci et al., 1993; Zhou et al., 2000)
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In 1918 the 5- to 15-year-old group jumped to 25 percent of influenza cases, compatible with exposure to an antigenically novel virus strain. The >65 age group only accounted for 0.6 percent of the influenza cases in 1918.
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. group had such a high influenza and pneumonia mortality rate in 1918 remains enigmatic, but it is one of the truly unique features of the 1918 influenza pandemic.
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. It is currently unclear what other influenza gene segments were novel in the 1918 pandemic virus in comparison to the previously circulating virus strain.
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69 PR34 (MS) SwNI38b SwCambridge39a SwCambridge39b WSN33 WS33 SwNI38a 100 South Carolina18 Brevig Mission18 New York18 SwIowa31 SwAlma-Ata84 SwIowa30 SwSt Hyacinthe90 95 Sw29/37 SwIllinois63 100 SwSt Hyacinthe91 SwQuebec90 SwNebraska92 100 SwIowa88 Maryland91 Swine SwEhime80 SwItaly81 SwHong Kong74 New Jersey76a New Jersey76b TyGermany90 TyGermany91 100 DkHong Kong77 DkHong Kong76 100 ChHong Kong76 DkBavaria77 100 DkWisconsin80b DkAlberta76 MallTennessee85 Avian TyMinnesota81 DkWisconsin80a Japan57 (H2N2)
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From page 80... ...
The HA receptor binding site consists of a subset of amino acids that are invariant in all avian HAs, but vary in mammalian-adapted HAs. Human-adapted influenza viruses preferentially bind sialic acid receptors with (2-6)
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. Some early human virus strains have short (11-16 amino acids)
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. Because influenza viruses possess eight discrete RNA segments that can move independently between virus strains by the process of
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From page 83... ...
Phylogenetic analyses of total or synonymous NA nucleotide changes also place the 1918 NA sequence with the mammalian viruses, but analysis of nonsynonymous changes or amino acid changes places the 1918 NA with the avian viruses (Reid et al., 2000)
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The 1918 NS1 protein varies from that of the WSN virus at 10 amino acid positions. The amino acid differences between the 1918 and A/WSN/33 NS segments may be important in the adaptation of the latter virus strain to mice and likely account for the observed differences in virulence in these experiments.
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From page 85... ...
. Although this segment is highly conserved among influenza virus strains, the 1918 sequence does not match any previously sequenced influenza virus strains.
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From page 86... ...
. NP is highly conserved, with a maximum amino acid difference of 11 percent among virus strains, probably because it must bind to multiple proteins, both viral and cellular.
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From page 87... ...
However, the very small number of amino acid differences from the avian consensus argues for recent introduction from birds-80 years after 1918, the NP genes of human influenza virus strains have accumulated more than 30 additional amino acid differences from the avian consensus (a rate of 2.3 amino acid changes per year)
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From page 88... ...
Thus, experiments testing models of virulence using reverse genetics approaches with 1918 influenza genes have begun. In future work it is hoped that the 1918 pandemic virus strain can be placed in the context of influenza virus strains that preceded it and followed it.
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PANDEMIC INFLUENZA AND MORTALITY: PAST EVIDENCE AND PROJECTIONS FOR THE FUTURE5 L Simonsen,6 D.R.
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From page 90... ...
Furthermore, antibodies to H3-like antigens -- the result of exposure to these antigens in childhood prior to 1892 -- relatively protected people aged 77 years and older. Because our experience with pandemic influenza is so limited, it is difficult to predict the mortality impact of future pandemics except to say that the likely range is wide (from ~20 to ~500 deaths per 100,000 population)
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From page 91... ...
Three influenza pandemics occurred in the twentieth century, and the patterns and magnitude of pandemic mortality are the only impact data available for all three of these events (Table 1-1)
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From page 92... ...
For the 1968 pandemic we present data comparing the mortality impact internationally -- and highlight the still unexplained finding of "smoldering" pandemic activity in Europe. We review more recent efforts to characterize the signature "age shift" of pandemic influenza and highlight the value of sero-archaeology as a tool to understand what we call "the virtues of antigenic sin" -- protection derived from exposure in childhood to influenza H-antigens that are recycled in later pandemic viruses.
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From page 93... ...
experienced a sharply elevated mortality risk and accounted for a markedly increased fraction of all influenza-related deaths. As we will discuss below, the 1968 pandemic age shift pattern was exacerbated by the protection of the very elderly by virtue of their experience with H3 antigens as children (Simonsen et al., 2003)
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Perhaps for that reason, the 1968 pandemic mortality impact was not particularly severe compared to the severe epidemic in 19671968 (the last A(H2N2) epidemic)
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. Even so, the absolute risk of dying from 1968 pandemic influenza was always highest among the very elderly, although this risk was likely significantly lower than it would have been without the protection provided by the anti-H3 antibodies still present in this age group.
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. We revisited the pandemic experience in the United States and the United Kingdom by extending the analysis of mortality data from both countries (Figure 1-8)
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pandemic seasons)
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, direct comparison of the absolute excess P&I mortality impact of the two pandemic waves is less revealing than their relative impact. In the United States, the first wave (19681969)
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From page 99... ...
The 1957 Asian Pandemic: Impact Over Several Seasons The 1957 influenza pandemic, which claimed the lives of more than one million people worldwide, has long been an unofficial model scenario for a future pandemic in the United States. In order to increase the utility of this model for pandemic planners, we have recently begun to compare the well-characterized mortality patterns observed in the United States during the pandemic (Serfling et al., 1967)
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-dominated seasons, 19591960 and 19621963. For example, 71 percent of the excess deaths among 1519 year olds in all three seasons occurred during the pandemic 19571958 season, while for people aged 75 and older only 33 percent of excess deaths occurred in the pandemic season (Table 1-4)
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From page 101... ...
. The 1918 Spanish Influenza Pandemic Revisited: Evidence for a Severe Herald Wave and Protection of the Elderly in New York City The exact time and place that the 1918 pandemic virus originated has never been conclusively determined.
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From page 102... ...
This pattern is consistent with the arrival of the pandemic virus in New York City at about this time, and the subsequent occurrence of a pandemic herald wave from February to April 1918 (Figure 1-9, Table 1-6)
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From page 103... ...
103 1919 (Population: City March Mortality Population York 1918 Excess Pandemic New 2004) in al., Major September All-Cause Rate/100,000 720 190 580 760 210 150 530 et Pandemic Olson Mortality from 1918 Population A(H1N1)
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From page 104... ...
2. Pandemic mortality impact is not always "tornado-like." Pandemic influenza is not always like a sudden storm, followed by a return to clear skies.
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From page 105... ...
In all three pandemics in the twentieth century, the majority of associated deaths occurred 6 months to a year after the pandemic virus first emerged. This suggests that intense and timely surveillance of both age-specific mortality and new influenza viruses could provide sufficient time for production and distribution of vaccines and antivirals to prevent much, if not most, of the mortality impact.
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From page 106... ...
The 2004 U.S. Pandemic Influenza Preparedness and Response Plan developed by the National Vaccine Program Office has not yet defined such priority groups (DHHS, 2004:24)
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2004. Pandemic Influenza Response and Preparedness Plan.
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From page 108... ...
2002. Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: The role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza.
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2004. Global host immune response: Patho genesis and transcriptional profiling of type A influenza viruses expressing the hemag glutinin and neuraminidase genes from the 1918 pandemic virus.
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2004. Containing pandemic influenza with antiviral agents.
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2004. Novel origin of the 1918 pandemic influenza virus nucleoprotein gene segment.
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1970. Pandemic influenza: An unresolved problem in prevention.
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From page 113... ...
2003. Are we ready for pandemic influenza?
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1995. Interspecies transmission of influenza viruses.
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