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The Story of Influenza

OVERVIEW

In the early 20th century, science was sufficiently sophisticated to anticipate that influenza, which had twice reached pandemic proportions in the late 19th century, would recur, but was largely powerless to blunt the devastating impact of the 1918 (H1N1) pandemic. 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) infection; and molecular technology that may one day pinpoint the viral components that produce virulence, and thereby identify targets for more effective vaccines and drugs.

Yet the world is vulnerable to the next pandemic, perhaps even more than in 1918, when the pace and frequency of global travel was considerably less than today. As the contributors to this chapter demonstrate, there is still much to be learned from past pandemics that can strengthen defenses against future threats. The chapter begins with a review of the events of 1918, the lessons they offer, and the historical and scientific questions they raise. It describes the epidemiology and symptomology of that deadly viral strain, limited efforts toward prevention and treatment, and the resulting social disruption and its exacerbation by the actions of public officials and the media.

The chapter continues with an account of molecular studies underway to determine the origin of the 1918 virus and the source(s) of its exceptional virulence. Clues are being sought by examining viruses preserved in frozen



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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary 1 The Story of Influenza OVERVIEW In the early 20th century, science was sufficiently sophisticated to anticipate that influenza, which had twice reached pandemic proportions in the late 19th century, would recur, but was largely powerless to blunt the devastating impact of the 1918 (H1N1) pandemic. 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) infection; and molecular technology that may one day pinpoint the viral components that produce virulence, and thereby identify targets for more effective vaccines and drugs. Yet the world is vulnerable to the next pandemic, perhaps even more than in 1918, when the pace and frequency of global travel was considerably less than today. As the contributors to this chapter demonstrate, there is still much to be learned from past pandemics that can strengthen defenses against future threats. The chapter begins with a review of the events of 1918, the lessons they offer, and the historical and scientific questions they raise. It describes the epidemiology and symptomology of that deadly viral strain, limited efforts toward prevention and treatment, and the resulting social disruption and its exacerbation by the actions of public officials and the media. The chapter continues with an account of molecular studies underway to determine the origin of the 1918 virus and the source(s) of its exceptional virulence. Clues are being sought by examining viruses preserved in frozen

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary and fixed tissues of victims of the 1918 flu. Characterization of five of the eight RNA segments of the 1918 influenza virus indicates that it was the common ancestor of both subsequent human and swine H1N1 lineages, and experiments testing models of virulence using reverse genetics approaches with 1918 influenza genes have begun in hopes of identifying genetic features that confer virulence in humans. 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. In particular, these studies reveal a signature change in excess mortality from the elderly to younger age groups, a “pandemic age shift,” that occurred with each of the three pandemics of the 20th century. If such a shift could be recognized in incipient pandemics, it might allow sufficient time for the production and distribution of vaccine and antiviral drugs before the worst pandemic impact occurs. 1918 REVISITED: LESSONS AND SUGGESTIONS FOR FURTHER INQUIRY John M. Barry Distinguished Visiting Scholar Center for Bioenvironmental Research at Tulane and Xavier Universities The 1918–1919 influenza pandemic killed more people in absolute numbers than any other disease outbreak in history. A contemporary estimate put the death toll at 21 million, a figure that persists in the media today, but understates the real number. Epidemiologists and scientists have revised that figure several times since then. Each and every revision has been upward. Frank Macfarlane Burnet, who won his Nobel Prize for immunology but who spent most of his life studying influenza, estimated the death toll as probably 50 million, and possibly as high as 100 million. A 2002 epidemiologic study also estimates the deaths at between 50 and 100 million (Johnson and Mueller, 2002). The world population in 1918 was only 28 percent of today’s population. Adjusting for population, a comparable toll today would be 175 to 350 million. By comparison, at this writing AIDS has killed approximately 24 million, and an estimated 40 million more people are infected with the virus.

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary A letter from a physician at one U.S. Army camp to a colleague puts a more human face on those numbers: These men start with what appears to be an ordinary attack of LaGrippe or Influenza, and when brought to the Hosp. they very rapidly develop the most vicious type of Pneumonia that has ever been seen … and a few hours later you can begin to see the Cyanosis extending from their ears and spreading all over the face, until it is hard to distinguish the colored men from the white. It is only a matter of a few hours then until death comes…. It is horrible. One can stand it to see one, two or twenty men die, but to see these poor devils dropping like flies…. We have been averaging about 100 deaths per day…. Pneumonia means in about all cases death…. We have lost an outrageous number of Nurses and Drs. It takes special trains to carry away the dead. For several days there were no coffins and the bodies piled up something fierce…. It beats any sight they ever had in France after a battle. An extra long barracks has been vacated for the use of the Morgue, and it would make any man sit up and take notice to walk down the long lines of dead soldiers all dressed and laid out in double rows…. Good By old Pal, God be with you till we meet again (Grist, 1979). That letter reflected a typical experience in American Army cantonments. The civilian experience was not much better. In preparing for another pandemic, it is useful to examine events of 1918 for lessons, warnings, and areas for further inquiry. 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. A partial listing of particularly violent outbreaks likely to have been influenza include one in 1510 when a pandemic believed to come from Africa “attacked at once and raged all over Europe not missing a family and scarce a person” (Beveridge, 1977). In 1580, another pandemic started in Asia, then spread to Africa, Europe, and even America (despite the fact that it took 6 weeks to cross the ocean). It was so fierce “that in the space of six weeks it afflicted almost all the nations of Europe, of whom hardly the twentieth person was free of the disease” and some Spanish cities were “nearly entirely depopulated by the disease” (Beveridge, 1977). In 1688, influenza struck England, Ireland, and Virginia; in all these places “the people dyed … as in a plague” (Duffy, 1953). A mutated or new virus continued to plague Europe and America again in 1693 and Massachusetts in 1699. “The sickness extended to almost all families. Few or none escaped, and many dyed especially in Boston, and some dyed in a strange or unusual

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary manner, in some families all were sick together, in some towns almost all were sick so that it was a time of disease” (Pettit, 1976). In London in 1847 and 1848, more people died from influenza than from the terrible cholera epidemic of 1832. In 1889 and 1890, a great and violent worldwide pandemic struck again (Beveridge, 1977). But 1918 seems to have been particularly violent. It began mildly, with a spring wave. In fact, it was so mild that some physicians wonder if this disease actually was influenza. Typically, several Italian doctors argued in separate journal articles that this “febrile disease now widely prevalent in Italy [is] not influenza” (Policlinico, 1918). British doctors echoed that conclusion; a Lancet article in July 1918 argued that the spring epidemic was not influenza because the symptoms, though similar to influenza, were “of very short duration and so far absent of relapses or complications” (Little et al., 1918). Within a few weeks of that Lancet article appearing, a second pandemic wave swept around the world. It also initially caused investigators to doubt that the disease was influenza—but this time because it was so virulent. It was followed by a third wave in 1919, and significant disease also struck in 1920. (Victims of the first wave enjoyed significant resistance to the second and third waves, offering compelling evidence that all were caused by the same virus. It is worth noting that the 1889–1890 pandemic also came in waves, but the third wave seemed to be the most lethal.) The 1918 virus, especially in its second wave, was not only virulent and lethal, but extraordinarily violent. It created a range of symptoms rarely seen with the disease. After H5N1 first appeared in 1997, pathologists reported some findings “not previously described with influenza” (To et al., 2001). In fact, investigators in 1918 described every pathological change seen with H5N1 and more (Jordon, 1927:266–268). Symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, “One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred” (Ireland, 1928:57). A German investigator recorded “hemorrhages occurring in different parts of the interior of the eye” with great frequency (Thomson and Thomson, 1934b). An American pathologist noted: “Fifty cases of subconjunctival hemorrhage were counted. Twelve had a true hemotypsis, bright red blood with no admixture of mucus…. Three cases had intestinal hemorrhage” (Ireland, 1928:13). The New York City Health Department’s chief pathologist said, “Cases with intense pain look and act like cases of dengue … hemorrhage from nose or bronchi … paresis or paralysis of either cerebral or spinal origin … impairment of motion may be severe or mild, permanent or temporary … physical and mental depression. Intense

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary and protracted prostration led to hysteria, melancholia, and insanity with suicidal intent” (Jordon, 1927:265). The 1918 virus also targeted young adults. In South African cities, those between the ages of 20 and 40 accounted for 60 percent of the deaths (Katzenellenbogen, 1988). In Chicago the deaths among those aged 20 to 40 nearly quintupled deaths of those aged 41 to 60 (Van Hartesveldt, 1992). A Swiss physician “saw no severe case in anyone over 50.”1 In the “registration area” of the United States—those states and cities that kept reliable statistics—the single greatest number of deaths occurred in the cohort aged 25 to 29, the second greatest in those aged 30 to 34, and the third in those aged 20 to 24. More people died in each one of those 5-year groups than the total deaths among all those over age 60, and the combined deaths of those aged 20 to 34 more than doubled the deaths of all those over 50 (U.S. Bureau of the Census, 1921). The single group most likely to die if infected were pregnant women. In 13 studies of hospitalized pregnant women during the 1918 pandemic, the death rate ranged from 23 to 71 percent (Jordon, 1927:273). Of the pregnant women who survived, 26 percent lost the child (Harris, 1919). (As far back as 1557, people connected influenza with miscarriage and the death of pregnant women.) The case mortality rate varied widely. An overall figure is impossible to obtain, or even estimate reliably, because no solid information about total cases exists. In U.S. Army camps where reasonably reliable statistics were kept, case mortality often exceeded 5 percent, and in some circumstances exceeded 10 percent. In the British Army in India, case mortality for white troops was 9.6 percent, for Indian troops 21.9 percent. In isolated human populations, the virus killed at even higher rates. In the Fiji islands, it killed 14 percent of the entire population in 16 days. In Labrador and Alaska, it killed at least one-third of the entire native population (Jordan, 1927; Rice, 1988). But perhaps most disturbing and most relevant for today is the fact that a significant minority—and in some subgroups of the population a majority—of deaths came directly from the virus, not from secondary bacterial pneumonias. 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. 1   Correspondenz-Blatt fur Schweizer Aerzte, Basel, 11/5/18. 48, #40, “influenza epidemic,” E. bircher, p. 1338, quoted in JAMA 71(23):1946.

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary Then, the Army called them “atypical pneumonias.” Today we would call this atypical pneumonia Acute Respiratory Distress Syndrome (ARDS). The Army’s pneumonia board judged that “more than half” of all the deaths among soldiers came from this atypical pneumonia (Ireland, 1928). One cannot extrapolate from this directly to the civilian population. Army figures represent a special case both in terms of demographics and environment, including overcrowded barracks. Even so, the fact that ARDS likely caused more than half the deaths among young adults sends a warning. ARDS mortality rates today range from 40 to 60 percent, even with support in modern intensive care units (ICUs). In a pandemic, ICUs would be quickly overwhelmed, representing a major challenge for public health planners. Treatment and Prevention in 1918 Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success. George Whipple, later a Nobel laureate, studied numerous vaccines and sera and found them “without therapeutic benefit.” But of some vaccines he said, “The statistical evidence, so far as it goes, indicates a probability … [of] some prophylactic value.”2 Some bacterial vaccines may have prevented particular secondary pneumonias. Meanwhile, the public used home remedies of every description. None showed any evidence of effect. Some nonmedical interventions did succeed. Total isolation, cutting a community off from the outside world, did work if done early enough. Gunnison, Colorado, a town that was a rail center and was large enough to have a college, succeeded in isolating itself. So did Fairbanks, Alaska. American Samoa escaped without a single case, while a few miles away in Western Samoa, 22 percent of the entire population died. More interestingly—and perhaps importantly—an Army study found that isolating both individual victims and entire commands that contained infected soldiers “failed when and where [these measures] were carelessly 2   JAMA 71(16):1317 current comment, Vaccines in influenza.

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary applied,” but “did some good … when and where they were rigidly carried out” (Soper, undated draft report). Even if isolation only slowed the virus, it had some value. One of the more interesting epidemiologic findings in 1918 was that the later in the second wave someone got sick, the less likely he or she was to die, and the more mild the illness was likely to be. This was true in terms of how late in the second wave the virus struck a given area, and, more curiously, it was also true within an area. That is, cities struck later tended to suffer less, and individuals in a given city struck later also tended to suffer less. Thus west coast American cities, hit later, had lower death rates than east coast cities, and Australia, which was not hit by the second wave until 1919, had the lowest death rate of any developed country. Again, more curiously, someone who got sick 4 days into an outbreak in one place was more likely to develop a viral pneumonia that progressed to ARDS than someone who got sick 4 weeks into the outbreak in the same place. They were also more likely to develop a secondary bacterial pneumonia, and to die from it. The best data on this comes from the U.S. Army. Of the Army’s 20 largest cantonments, in the first five affected, roughly 20 percent of all soldiers with influenza developed pneumonia. Of those, 37.3 percent died (Soper, 1918; undated draft report). In the last five camps affected—on average 3 weeks later—only 7.1 percent of influenza victims developed pneumonia. Only 17.8 percent of the soldiers who developed pneumonia died (Soper, 1918). Inside each camp the same trend held true. Soldiers struck down early died at much higher rates than soldiers in the same camp struck down late. Similarly, the first cities struck—Boston, Baltimore, Pittsburgh, Philadelphia, Louisville, New York, New Orleans, and smaller cities hit at the same time—all suffered grievously. 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. One of the most careful epidemiologic studies of the epidemic was conducted in Connecticut. The investigator noted that “one factor that appeared to affect the mortality rate was proximity in time to the original outbreak at New London, the point at which the disease was first introduced into Connecticut…. The virus was most virulent or most readily communicable when it first reached the state, and thereafter became generally attenuated” (Thompson and Thompson, 1934a: 215). The same pattern held true throughout the country and the world. It was not a rigid predictor. The virus was never completely consistent. But places hit later tended to suffer less.

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary One obvious hypothesis that might explain this phenomenon is that medical care improved as health care workers learned how to cope with the disease. But this hypothesis collapses upon examination. In a given city, as the epidemic proceeded, medical care disintegrated. Doctors and nurses were overworked and sick themselves, and victims—possibly even a majority of victims—received no care at all late in an epidemic. 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. A second obvious explanatory hypothesis, that the most vulnerable people were struck first, also fails. For that hypothesis to be true, Americans on the east coast had to have been more vulnerable than those on the west coast, and Americans and western Europeans had to have been more vulnerable than Australians. But another hypothesis, although entirely speculative, may be worth exploring. If one steps back and looks at the entire United States, it seems that people across the country infected with the virus in September and early to mid-October suffered the most severe attacks. Those infected later, in whatever part of the country they were, suffered less. At the peak of the pandemic, then, the virus seemed to still be mutating rapidly, virtually with each passage through humans, and it was mutating toward a less lethal form. We do know that after a mild spring wave, after a certain number of passages through humans, a lethal virus evolved. Possibly after additional passages it became less virulent. This makes sense particularly if the virus was immature when it erupted in September, if it entered the human population only a few months before the lethal wave. This hypothesis may suggest some areas for investigation. Social Disruption and Public Health Lessons In the United States, national and local government and public health authorities badly mishandled the epidemic, offering a useful case study. The context is important. Every country engaged in World War I tried to control public perception. To avoid hurting morale, even in the nonlethal first wave the press in countries fighting in the war did not mention the outbreak. (But Spain was not at war and its press wrote about it, so the pandemic became known as the Spanish flu). The United States was no different. In 1917 California Senator Hiram Johnson made the since-famous observation that “The first casualty when war comes is truth.” The U.S. government passed a law that made it pun-

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary ishable by 20 years in jail to “utter, print, write or publish any disloyal, profane, scurrilous, or abusive language about the government of the United States.” One could go to jail for cursing or criticizing the government, even if what one said was true. A Congressman was jailed. Simultaneously, the government mounted a massive propaganda effort. An architect of that effort said, “Truth and falsehood are arbitrary terms…. There is nothing in experience to tell us that one is always preferable to the other…. The force of an idea lies in its inspirational value. It matters very little if it is true or false” (Vaughn, 1980). The combination of rigid control and disregard for truth had dangerous consequences. Focusing on the shortest term, local officials almost universally told half-truths or outright lies to avoid damaging morale and the war effort. They were assisted—not challenged—by the press, which although not censored in a technical sense cooperated fully with the government’s propaganda machine. Routinely, as influenza approached a city or town—one could watch it march from place to place—local officials initially told the public not to worry, that public health officials would prevent the disease from striking them. When influenza first appeared, officials routinely insisted at first it was only ordinary influenza, not the Spanish flu. As the epidemic exploded, officials almost daily assured the public that the worst was over. This pattern repeated itself again and again. Chicago offers one example: Its public health commissioner said he’d do “nothing to interfere with the morale of the community…. It is our duty to keep the people from fear. Worry kills more people than the epidemic” (Robertson, 1918). That idea—“Fear kills more than the disease”—became a mantra nationally and in city after city. As Literary Digest, one of the largest circulation periodicals in the country, advised, “Fear is our first enemy” (Van Hartesveldt, 1992). In Philadelphia, when the public health commissioner closed all schools, houses of worship, theaters, and other public gathering places, one newspaper went so far as to say that this order was “not a public health measure” and reiterated that “there is no cause for panic or alarm.” But as people heard these reassurances, they could see neighbors, friends, and spouses dying horrible deaths. 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). In Philadelphia, bodies remained uncollected in homes for days, until eventually open trucks and even horse-drawn carts were sent down city streets and people were told to bring out the dead. The bodies were stacked without coffins and buried in cemeteries in mass graves dug by steam shovels.

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary This horrific disconnect between reassurances and reality destroyed the credibility of those in authority. People felt they had no one to turn to, no one to rely on, no one to trust. Ultimately society depends on trust. Without it, society began to come apart. Normally in 1918 America, when someone was ill, neighbors helped. That did not happen during the pandemic. Typically, the head of one city’s volunteer effort, frustrated after repeated pleas for help yielded nothing, turned bitter and contemptuous: Hundreds of women who are content to sit back had delightful dreams of themselves in the roles of angels of mercy, had the unfathomable vanity to imagine that they were capable of great sacrifice. Nothing seems to rouse them now. They have been told that there are families in which every member is ill, in which the children are actually starving because there is no one to give them food. The death rate is so high and they still hold back.3 That attitude persisted outside of cities as well. 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). As the pressure from the virus continued, an internal Red Cross report concluded, “A fear and panic of the influenza, akin to the terror of the Middle Ages regarding the Black Plague, [has] been prevalent in many parts of the country” (The Mobilization of the American National Red Cross, 1920). Similarly, Victor Vaughan, a sober scientist not given to overstatement, worried, “If the epidemic continues its mathematical rate of acceleration, civilization could easily … disappear … from the face of the earth within a matter of a few more weeks” (Collier, 1974). Of course, the disease generated fear independent of anything officials did or did not do, but the false reassurances given by the authorities and the media systematically destroyed trust. That magnified the fear and turned it into panic and terror. It is worth noting that this terror, at least in paralyzing form, did not seem to materialize in the few places where authorities told the truth. One lesson is clear from this experience: In handling any crisis, it is absolutely crucial to retain credibility. Giving false reassurance is the worst thing one can do. If I may speculate, let me suggest that almost as bad as outright lying is holding information so closely that people think officials know more than they say. 3   October 16, 1918, minutes of Philadelphia General Hospital Woman’s Advisory Council.

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary The Site of Origin It is very possible that we will never know with certainty where the 1918 virus crossed into man. In the 1920s and 1930s, outstanding investigators in several countries launched massive reviews of evidence searching for the site of origin. They could not definitively answer the question. But they were unanimous in believing that no known outbreak in China could, as one investigator said, “be reasonably regarded as the true forerunner” of the epidemic. 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). My own research also makes me think that the United States was the most likely site of origin. The unearthing of previously unknown epidemiologic evidence has led me to advance my own hypothesis that the pandemic began in rural Kansas and traveled with draftees to what is now Fort Riley. But whether the pandemic began in France or the United States is not really important. What does matter is that the pandemic most likely did not begin in Asia. This has important implications for modern surveillance efforts. Although Asia’s population density and the close proximity of humans and animals there makes the region particularly dangerous, the evidence of 1918—confirmed by the H7N7 outbreak in Europe of 2003—demonstrates the need for surveillance worldwide. Something else should be addressed regarding surveillance. A physician now active in public health who received his medical degree in Honduras in 1986 says that he and his colleagues were taught that there was no difference between a cold and influenza. He believes physicians in Central America and possibly elsewhere in the world routinely ignore influenza. Clearly, if we are to have an adequate surveillance system, physicians need to be alert to the disease. Data Outstanding laboratory investigators have made enormous progress over the years in understanding the virus and developing effective antiviral drugs as well as new technologies to make vaccines. But one area remains in which investigators have lagged behind—in applying modern insights and statistical methods to old data. To use an analogy, a similar situation is found in the flooding of the Sacramento River, one of the few rivers in the country where flood control

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary The New York City data also demonstrate that mortality among people aged 45 and older during the 1918–1919 pandemic influenza season was no worse than in surrounding years. For people under age 45, however, the 1918–1919 influenza season was very bad—people in this age group were far more likely to die of influenza than in previous years. Indeed, the age groups at highest absolute risk of dying during the 1918–1919 A(H1N1) pandemic were young children and young and middle-aged adults (Table 1-6). These findings suggest that the early 1918 pandemic herald wave was spreading as early as February 1918, 6–7 months before the beginning of the explosive 1918–1919 pandemic. Relative to preceding influenza epidemic seasons, both the herald and pandemic waves caused proportionally more mortality in younger age groups but less mortality among those over 45 years of age, possibly as the result of recycling of an H1-like antigen from half a century earlier (Olson et al., 2004). Conclusion: Lessons from Pandemics Past for Pandemics Still to Come Epidemiologic studies of past pandemics offer at least three important insights into what we can expect when the next influenza pandemic occurs. We believe these observations can help to guide pandemic detection and preparedness planning. 1. Mortality impact is difficult to predict, but a shift to younger ages is highly likely. Because our experience with pandemic influenza is so limited (N = 3), it is difficult to predict the mortality impact of a future pandemic. One can say, however, that the likely range is wide (from ~20 to ~500 deaths per 100,000 people) and that people under 65 years of age will account for a high proportion of these death. 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. Instead, mortality rates can remain elevated for several years—during which time an effective vaccine would be in high demand. For example, in the 1957 pandemic worldwide, and in the 1968 pandemic in North America, much of the pandemic mortality impact occurred in a series of smaller but still severe twisters in subsequent years. This seems well explained by attack rates: The pattern of cumulative age-specific mortality impact during the first waves mirrored the age-specific attack rates, at least for the 1957 pandemic (Serfling et al., 1967). Thus, the majority of middle-aged and elderly people—age groups that account for most of the cumulative pandemic mortality—were only affected by the emerging strain during the second or third season after its emergence. 3. Often there is a warning. For the 1918 pandemic, a herald wave that caused substantial mortality occurred at least 6 months before the

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary major force of the pandemic hit in September. The 1957 pandemic virus had been characterized in Asia by the spring and was known to be circulating in the United States as early as June—months before the pandemic mortality impact began. For the 1968 pandemic, the majority of European deaths occurred after a 1-year delay. Thus, in all three pandemics, some form of warning was available. Although mortality data are useful to characterize the patterns and impact of past pandemics, in most countries such data would not be available to allow timely detection of mortality age shifts to reveal pandemic activity. Instead, influenza virus surveillance efforts are most likely to provide the first warning of a future pandemic. And because younger people are disproportionately infected by pandemic strains when these first emerge, focusing pandemic virus surveillance efforts on isolates from children and young adults with severe outcomes of upper respiratory diseases would help to ensure that pandemic activity is detected as quickly as possible. The idea that the next pandemic may not do all or even most of its damage in the first season is certainly good news for preparedness planning. 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. Moreover, these medical interventions are likely to continue to play an important role for many years after the pandemic season. One should also note that the 1957 and 1968 pandemics tended to respect normal seasonality patterns, giving one hemisphere of the world an extra 6 months to prepare. Finally, the existence of the pandemic age shift documented for all pandemics studied raises a crucial question: Who should get vaccines and antivirals first if these are in short supply, younger people or the elderly? If a future pandemic were to be like the severe 1918/1919 pandemic, in which young and middle-aged adults were the age groups at highest absolute risk of dying, then younger people should clearly get priority. But if a future pandemic were like the 1957 or the 1968 pandemics, the answer would not be so obvious. In those years, young and middle-aged adults were facing the most dramatic risk increase relative to non-pandemic influenza, yet they remained at a lower absolute risk than the elderly. The situation would be made more complex if the pandemic virus were to contain a recycled influenza antigen. In this instance, elderly age groups with prior exposure to similar antigens might be at less risk than in preceding non-pandemic seasons. Of course, with or without recycling, a pattern like those seen in 1957 or 1968 would result in the elderly having a higher absolute risk of death.

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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary If the metric used to measure effectiveness of vaccination were “numbers of deaths prevented,” then perhaps the elderly should be given priority—assuming they can produce an adequate antibody response to the pandemic vaccine. But if the concern is to minimize the years-of-life-lost, then the vaccine may be better used in young and middle-aged adults. This point was illustrated in a paper that sought to determine vaccination priorities by age and risk status; when basing priority on “returns due to vaccination,” an endpoint that is heavily influenced by years of life lost, the young and middle aged rose to the top of the priority list (Meltzer et al., 1999). Other authors have proposed that children be given priority to receive pandemic vaccine (Stuart-Harris, 1970; Longini et al., 1978; Reichert et al., 2001) and antivirals (Longini et al., 2004) in order to reduce transmission in the community and thereby indirectly reduce influenza impact among the elderly. 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). Given the very different proposals for how to best employ pandemic vaccines and antivirals should a shortage occur, we urge that a framework for determining priority groups be developed immediately. Such a scheme should be agreed on beforehand and be flexible enough to adapt to the likely level of disaster at hand. Any such an assessment would depend on rapid interpretation of early data on transmissibility and case fatality in the pandemic epicenter. Will the next pandemic be 1918-like or 1957/1968-like? That is the question. REFERENCES An Account of the Influenza Epidemic in Perry County, Kentucky. 1919. 8/14/19, NA, RG 200, Box 689. Assaad F, Cockburn WC, Sundaresan TK. 1973. Use of excess mortality from respiratory diseases in the study of influenza. Bull World Health Organ 49(3):219–233. Barry JM. 2004. The Great Influenza: The Epic Story of the Deadliest Plague in History. New York: Viking Press. P. 560. Basler CF, Reid AH, Dybing JK, Janczewski TA, Fanning TG, Zheng H, Salvatore M, Perdue ML, Swayne DE, Garcia-Sastre A, Palese P, Taubenberger JK. 2001. Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci USA 98:2746–2751. Beveridge W. 1977. Influenza: The Last Great Plague, an Unfinished Story of Discovery. New York: Prodist. Brown IH, Chakraverty P, Harris PA, Alexander DJ. 1995. Disease outbreaks in pigs in Great Britain due to an influenza A virus of H1N2 subtype. Vet Rec 136:328–329. Brown IH, Harris PA, McCauley JW, Alexander DJ. 1998. Multiple genetic reassortment of avian and human influenza A viruses in European pigs, resulting in the emergence of an H1N2 virus of novel genotype. J Gen Virol 79:2947–2955.

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