Summary Background 18 500 laboratory-confirmed deaths caused by the 2009 pandemic influenza A H1N1 were reported worldwide for the period April, 2009, to August, 2010. This number is likely to be only a fraction of the true number of the deaths associated with 2009 pandemic influenza A H1N1. We aimed to estimate the global number of deaths during the first 12 months of virus circulation in each country. Methods We calculated crude respiratory mortality rates associated with the 2009 pandemic influenza A H1N1 strain by age (0–17 years, 18–64 years, and >64 years) using the cumulative (12 months) virus-associated symptomatic attack rates from 12 countries and symptomatic case fatality ratios (sCFR) from five high-income countries. To adjust crude mortality rates for differences between countries in risk of death from influenza, we developed a respiratory mortality multiplier equal to the ratio of the median lower respiratory tract infection mortality rate in each WHO region mortality stratum to the median in countries with very low mortality. We calculated cardiovascular disease mortality rates associated with 2009 pandemic influenza A H1N1 infection with the ratio of excess deaths from cardiovascular and respiratory diseases during the pandemic in five countries and multiplied these values by the crude respiratory disease mortality rate associated with the virus. Respiratory and cardiovascular mortality rates associated with 2009 pandemic influenza A H1N1 were multiplied by age to calculate the number of associated deaths. Findings We estimate that globally there were 201 200 respiratory deaths (range 105 700–395 600) with an additional 83 300 cardiovascular deaths (46 000–179 900) associated with 2009 pandemic influenza A H1N1. 80% of the respiratory and cardiovascular deaths were in people younger than 65 years and 51% occurred in southeast Asia and Africa. Interpretation Our estimate of respiratory and cardiovascular mortality associated with the 2009 pandemic influenza A H1N1 was 15 times higher than reported laboratory-confirmed deaths. Although no estimates of sCFRs were available from Africa and southeast Asia, a disproportionate number of estimated pandemic deaths might have occurred in these regions. Therefore, efforts to prevent influenza need to effectively target these regions in future pandemics. Funding None.

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Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study

Copyright © 2010 Massachusetts Medical Society. During the spring of 2009, a novel influenza A (H1N1) virus of swine origin caused human infection and acute respiratory illness in Mexico.1,2 After initially spreading among persons in the United States and Canada,3,4 the virus spread globally, resulting in the first influenza pandemic since 1968 with circulation outside the usual influenza season in the Northern Hemisphere (see the Supplementary Appendix, available with the full text of this article at NEJM.org). As of March 2010, almost all countries had reported cases, and more than 17,700 deaths among laboratory-confirmed cases had been reported to the World Health Organization (WHO).5 The number of laboratory-confirmed cases significantly underestimates the pandemic’s impact. In the United States, an estimated 59 million illnesses, 265,000 hospitalizations, and 12,000 deaths had been caused by the 2009 H1N1 virus as of mid-February 2010.6 This article reviews virologic, epidemiologic, and clinical data on 2009 H1N1 virus infections and summarizes key issues for clinicians worldwide.

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Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection.

Background: Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures. Methods and Findings: Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients ,5 y and 5–14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50–64 y and $65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the $65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3). Conclusions: Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes. Please see later in the article for the Editors’ Summary.

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Risk Factors for Severe Outcomes following 2009 Influenza A (H1N1) Infection: A Global Pooled Analysis

The 2009 A (H1N1) influenza virus pandemic: A review.

To calculate the burden of 2009 pandemic influenza A (pH1N1) in the United States, we extrapolated from the Centers for Disease Control and Prevention's Emerging Infections Program laboratory-confirmed hospitalizations across the entire United States, and then corrected for underreporting. From 12 April 2009 to 10 April 2010, we estimate that approximately 60.8 million cases (range: 43.3-89.3 million), 274,304 hospitalizations (195,086-402,719), and 12,469 deaths (8868-18,306) occurred in the United States due to pH1N1. Eighty-seven percent of deaths occurred in those under 65 years of age with children and working adults having risks of hospitalization and death 4 to 7 times and 8 to 12 times greater, respectively, than estimates of impact due to seasonal influenza covering the years 1976-2001. In our study, adults 65 years of age or older were found to have rates of hospitalization and death that were up to 75% and 81%, respectively, lower than seasonal influenza. These results confirm the necessity of a concerted public health response to pH1N1.

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Estimating the Burden of 2009 Pandemic Influenza A (H1N1) in the United States (April 2009–April 2010)

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 7–96 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.

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The Severity of Pandemic H1N1 Influenza in the United States, from April to July 2009: A Bayesian Analysis

BackgroundAccurate measures of the severity of pandemic influenza A/H1N1 (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. Methods and FindingsWe 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 in New York, were used to estimate ratios of symptomatic cases:hospitalizations. Combining these data with estimates of the fraction detected for each level of severity, we estimated the proportion of symptomatic cases that 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 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 7-9x lower. sCFR and sCIR appear to be highest in persons 18 and older, and lowest in children 5-17. sCHR appears to be lowest in persons 5-17; our data were too sparse to allow us to determine the group in which it was the highest. ConclusionsThese 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 greatest impact in young children and non-elderly adults. 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 proportion infected or symptomatic were lower.

The severity of pandemic H1N1 influenza in the United States, April - July 2009.

Background: During an influenza pandemic, a substantial proportion of transmission is thought to occur in households. We used data on influenza progression in individuals and their contacts collected by the City of Milwaukee Health Department (MHD) to study the transmission of pandemic influenza A/H1N1 virus in 362 households in Milwaukee, WI, and the effects of oseltamivir treatment and chemoprophylaxis. Methods: 135 households had chronological information on symptoms and oseltamivir usage for all household members. The effect of oseltamivir treatment and other factors on the household secondary attack rate was estimated using univariate and multivariate logistic regression with households as the unit of analysis. The effect of oseltamivir treatment and other factors on the individual secondary attack rate was estimated using univariate and multivariate logistic regression with individual household contacts as the unit of analysis, and a generalized estimating equations approach was used to fit the model to allow for clustering within households. Results: Oseltamivir index treatment on onset day or the following day (early treatment) was associated with a 42% reduction (OR: 0.58, 95% CI: 0.19, 1.73) in the odds of one or more secondary infections in a household and a 50% reduction (OR: 0.5, 95% CI: 0.17, 1.46) in the odds of a secondary infection in individual contacts. The confidence bounds are wide due to a small sample of households with early oseltamivir index usage - in 29 such households, 5 had a secondary attack. Younger household contacts were at higher risk of infection (OR: 2.79, 95% CI: 1.50-5.20). Conclusions: Early oseltamivir treatment may be beneficial in preventing H1N1pdm influenza transmission; this may have relevance to future control measures for influenza pandemics. Larger randomized trials are needed to confirm this finding statistically.

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Paul Biedrzycki

Papers

The Severity of Pandemic H1N1 Influenza in the United States, from April to July 2009: A Bayesian Analysis

The severity of pandemic H1N1 influenza in the United States, April - July 2009.

Oseltamivir for treatment and prevention of pandemic influenza A/H1N1 virus infection in households, Milwaukee, 2009