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Marc Lipsitch and colleagues use complementary data from two US cities, Milwaukee and New York City, to assess the severity of pandemic (H1N1) 2009 influenza in the United States., Background Accurate measures of the severity of pandemic (H1N1) 2009 influenza (pH1N1) are needed to assess the likely impact of an anticipated resurgence in the autumn in the Northern Hemisphere. Severity has been difficult to measure because jurisdictions with large numbers of deaths and other severe outcomes have had too many cases to assess the total number with confidence. Also, detection of severe cases may be more likely, resulting in overestimation of the severity of an average case. We sought to estimate the probabilities that symptomatic infection would lead to hospitalization, ICU admission, and death by combining data from multiple sources. Methods and Findings We used complementary data from two US cities: Milwaukee attempted to identify cases of medically attended infection whether or not they required hospitalization, while New York City focused on the identification of hospitalizations, intensive care admission or mechanical ventilation (hereafter, ICU), and deaths. New York data were used to estimate numerators for ICU and death, and two sources of data—medically attended cases in Milwaukee or self-reported influenza-like illness (ILI) in New York—were used to estimate ratios of symptomatic cases to hospitalizations. Combining these data with estimates of the fraction detected for each level of severity, we estimated the proportion of symptomatic patients who died (symptomatic case-fatality ratio, sCFR), required ICU (sCIR), and required hospitalization (sCHR), overall and by age category. Evidence, prior information, and associated uncertainty were analyzed in a Bayesian evidence synthesis framework. Using medically attended cases and estimates of the proportion of symptomatic cases medically attended, we estimated an sCFR of 0.048% (95% credible interval [CI] 0.026%–0.096%), sCIR of 0.239% (0.134%–0.458%), and sCHR of 1.44% (0.83%–2.64%). Using self-reported ILI, we obtained estimates approximately 7–9× lower. sCFR and sCIR appear to be highest in persons aged 18 y and older, and lowest in children aged 5–17 y. sCHR appears to be lowest in persons aged 5–17; our data were too sparse to allow us to determine the group in which it was the highest. Conclusions These estimates suggest that an autumn–winter pandemic wave of pH1N1 with comparable severity per case could lead to a number of deaths in the range from considerably below that associated with seasonal influenza to slightly higher, but with the greatest impact in children aged 0–4 and adults 18–64. These estimates of impact depend on assumptions about total incidence of infection and would be larger if incidence of symptomatic infection were higher or shifted toward adults, if viral virulence increased, or if suboptimal treatment resulted from stress on the health care system; numbers would decrease if the total proportion of the population symptomatically infected were lower than assumed. Please see later in the article for the Editors' Summary, Editors' Summary Background Every winter, millions of people catch influenza—a viral infection of the airways—and about half a million people die as a result. In the US alone, an average of 36,000 people are thought to die from influenza-related causes every year. These seasonal epidemics occur because small but frequent changes in the virus mean that an immune response produced one year provides only partial protection against influenza the next year. Occasionally, influenza viruses emerge that are very different and to which human populations have virtually no immunity. These viruses can start global epidemics (pandemics) that kill millions of people. Experts have been warning for some time that an influenza pandemic is long overdue and in, March 2009, the first cases of influenza caused by a new virus called pandemic (H1N1) 2009 (pH1N1; swine flu) occurred in Mexico. The virus spread rapidly and on 11 June 2009, the World Health Organization declared that a global pandemic of pH1N1 influenza was underway. By the beginning of November 2009, more than 6,000 people had died from pH1N1 influenza. Why Was This Study Done? With the onset of autumn—drier weather and the return of children to school help the influenza virus to spread—pH1N1 cases, hospitalizations, and deaths in the Northern Hemisphere have greatly increased. Although public-health officials have been preparing for this resurgence of infection, they cannot be sure of its impact on human health without knowing more about the severity of pH1N1 infections. The severity of an infection can be expressed as a case-fatality ratio (CFR; the proportion of cases that result in death), as a case-hospitalization ratio (CHR; the proportion of cases that result in hospitalization), and as a case-intensive care ratio (CIR; the proportion of cases that require treatment in an intensive care unit). Because so many people have been infected with pH1N1 since it emerged, the numbers of cases and deaths caused by pH1N1 infection are not known accurately so these ratios cannot be easily calculated. In this study, the researchers estimate the severity of pH1N1 influenza in the US between April and July 2009 by combining data on pH1N1 infections from several sources using a statistical approach known as Bayesian evidence synthesis. What Did the Researchers Do and Find? By using data on medically attended and hospitalized cases of pH1N1 infection in Milwaukee and information from New York City on hospitalizations, intensive care use, and deaths, the researchers estimate that the proportion of US cases with symptoms that died (the sCFR) during summer 2009 was 0.048%. That is, about 1 in 2,000 people who had symptoms of pH1N1 infection died. The “credible interval” for this sCFR, the range of values between which the “true” sCFR is likely to lie, they report, is 0.026%–0.096% (between 1 in 4,000 and 1 in 1,000 deaths for every symptomatic case). About 1 in 400 symptomatic cases required treatment in intensive care, they estimate, and about 1 in 70 symptomatic cases required hospital admission. When the researchers used a different approach to estimate the total number of symptomatic cases—based on New Yorkers' self-reported incidence of influenza-like-illness from a telephone survey—their estimates of pH1N1 infection severity were 7- to 9-fold lower. Finally, they report that the sCFR and the sCIR were highest in people aged 18 or older and lowest in children aged 5–17 years. What Do These Findings Mean? Many uncertainties (for example, imperfect detection and reporting) can affect estimates of influenza severity. Even so, the findings of this study suggest that an autumn–winter pandemic wave of pH1N1 will have a death toll only slightly higher than or considerably lower than that caused by seasonal influenza in an average year, provided pH1N1 continues to behave as it did during the summer. Similarly, the estimated burden on hospitals and intensive care facilities ranges from somewhat higher than in a normal influenza season to considerably lower. The findings of this study also suggest that, unlike seasonal influenza, which kills mainly elderly adults, a high proportion of deaths from pH1N1infection will occur in nonelderly adults, a shift in age distribution that has been seen in previous pandemics. With these estimates in hand and with continued close monitoring of the pandemic, public-health officials should now be in a better position to plan effective strategies to deal with the pH1N1 pandemic. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000207. The US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including specific information on pandemic H1N1 (2009) influenza Flu.gov, a US government Web site, provides access to information on H1N1, avian and pandemic influenza The World Health Organization provides information on seasonal influenza and has detailed information on pandemic H1N1 (2009) influenza (in several languages) The UK Health Protection Agency provides information on pandemic influenza and on pandemic H1N1 (2009) influenza More information for patients about H1N1 influenza is available through Choices, an information resource provided by the UK National Health Service