Correction to: Determinants of Influenza Mortality Trends: Age-Period-Cohort Analysis of Influenza Mortality in the United States, 1959-2016.

First, we use Lexis surfaces based on Serfling models to highlight influenza mortality patterns as well as to identify lingering effects of early-life exposure to specific influenza virus subtypes (e.g., H1N1, H3N2).

Determinants of Influenza Mortality Trends: Age-Period-Cohort Analysis of Influenza Mortality in the United States, 1959-2016.

This study examines the roles of age, period, and cohort in influenza mortality trends over the years 1959-2016 in the United States. First, we use Lexis surfaces based on Serfling models to highlight influenza mortality patterns as well as to identify lingering effects of early-life exposure to specific influenza virus subtypes (e.g., H1N1, H3N2). Second, we use age-period-cohort (APC) methods to explore APC linear trends and identify changes in the slope of these trends (contrasts). Our analyses reveal a series of breakpoints where the magnitude and direction of birth cohort trends significantly change, mostly corresponding to years in which important antigenic drifts or shifts took place (i.e., 1947, 1957, 1968, and 1978). Whereas child, youth, and adult influenza mortality appear to be influenced by a combination of cohort- and period-specific factors, reflecting the interaction between the antigenic experience of the population and the evolution of the influenza virus itself, mortality patterns of the elderly appear to be molded by broader cohort factors. The latter would reflect the processes of physiological capital improvement in successive birth cohorts through secular changes in early-life conditions. Antigenic imprinting, cohort morbidity phenotype, and other mechanisms that can generate the observed cohort effects, including the baby boom, are discussed.

Pandemic Paradox: Early Life H2N2 Pandemic Influenza Infection Enhanced Susceptibility to Death during the 2009 H1N1 Pandemic.

Recent outbreaks of H5, H7, and H9 influenza A viruses in humans have served as a vivid reminder of the potentially devastating effects that a novel pandemic could exert on the modern world. Those who have survived infections with influenza viruses in the past have been protected from subsequent antigenically similar pandemics through adaptive immunity. For example, during the 2009 H1N1 "swine flu" pandemic, those exposed to H1N1 viruses that circulated between 1918 and the 1940s were at a decreased risk for mortality as a result of their previous immunity. It is also generally thought that past exposures to antigenically dissimilar strains of influenza virus may also be beneficial due to cross-reactive cellular immunity. However, cohorts born during prior heterosubtypic pandemics have previously experienced elevated risk of death relative to surrounding cohorts of the same population. Indeed, individuals born during the 1890 H3Nx pandemic experienced the highest levels of excess mortality during the 1918 "Spanish flu." Applying Serfling models to monthly mortality and influenza circulation data between October 1997 and July 2014 in the United States and Mexico, we show corresponding peaks in excess mortality during the 2009 H1N1 "swine flu" pandemic and during the resurgent 2013-2014 H1N1 outbreak for those born at the time of the 1957 H2N2 "Asian flu" pandemic. We suggest that the phenomenon observed in 1918 is not unique and points to exposure to pandemic influenza early in life as a risk factor for mortality during subsequent heterosubtypic pandemics.IMPORTANCE The relatively low mortality experienced by older individuals during the 2009 H1N1 influenza virus pandemic has been well documented. However, reported situations in which previous influenza virus exposures have enhanced susceptibility are rare and poorly understood. One such instance occurred in 1918-when those born during the heterosubtypic 1890 H3Nx influenza virus pandemic experienced the highest levels of excess mortality. Here, we demonstrate that this phenomenon was not unique to the 1918 H1N1 pandemic but that it also occurred during the contemporary 2009 H1N1 pandemic and 2013-2014 H1N1-dominated season for those born during the heterosubtypic 1957 H2N2 "Asian flu" pandemic. These data highlight the heretofore underappreciated phenomenon that, in certain instances, prior exposure to pandemic influenza virus strains can enhance susceptibility during subsequent pandemics. These results have important implications for pandemic risk assessment and should inform laboratory studies aimed at uncovering the mechanism responsible for this effect.

Plasmodium falciparum malaria in 1st-2nd century CE southern Italy.

The historical record attests to the devastation malaria exacted on ancient civilizations, particularly the Roman Empire [1]. However, evidence for the presence of malaria during the Imperial period in Italy (1st-5th century CE) is based on indirect sources, such as historical, epigraphic, or skeletal evidence. Although these sources are crucial for revealing the context of this disease, they cannot establish the causative species of Plasmodium. Importantly, definitive evidence for the presence of malaria is now possible through the implementation of ancient DNA technology. As malaria is presumed to have been at its zenith during the Imperial period [1], we selected first or second molars from 58 adults from three cemeteries from this time: Isola Sacra (associated with Portus Romae, 1st-3rd century CE), Velia (1st-2nd century CE), and Vagnari (1st-4th century CE). We performed hybridization capture using baits designed from the mitochondrial (mtDNA) genomes of Plasmodium spp. on a prioritized subset of 11 adults (informed by metagenomic sequencing). The mtDNA sequences generated provided compelling phylogenetic evidence for the presence of P. falciparum in two individuals. This is the first genomic data directly implicating P. falciparum in Imperial period southern Italy in adults.

The first wave of the 1918 influenza pandemic among soldiers of the Canadian expeditionary force.

OBJECTIVES: This article evaluates the evidence for the presence of the first, mild wave of the 1918 influenza pandemic among soldiers in the Canadian Expeditionary Force (CEF). METHODS: Death records for soldiers in the CEF who died in Canada in 1917 and 1918 were extracted from the Commonwealth War Graves Commission and record-linked to the Canada War Graves Registers, Circumstances of Casualty database. Monthly mortality rates from pneumonia and influenza (P&I) were compared with mortality rates from all other causes for 1917 and 1918, and by region for 1918. RESULTS: The herald wave of influenza was present among CEF soldiers in 1918. P&I mortality was significantly higher in March and April 1918 than during the same period in 1917. P&I mortality rates varied across the country and were significantly higher among soldiers who died in the Maritime region of Canada. In March, Maritime P&I mortality was significantly higher than its counterpart in the West; in April it was significantly higher than P&I mortality in both the Central and Western regions. CONCLUSIONS: The CEF findings suggest that local, geographic heterogeneity characterized the first wave of the 1918 influenza pandemic in Canada and illustrate the ways in which well-established, historical patterns of cross-border social contact with the United States, coupled with the special conditions created by warfare, disproportionately funnelled influenza into particular regions. Identification of the mild first wave among soldiers in the CEF calls for more research on the civilian experience of both waves of influenza in Canada.

Age-specific mortality during the 1918 influenza pandemic: unravelling the mystery of high young adult mortality.

The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889-90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics.

A draft genome of Yersinia pestis from victims of the Black Death.

Technological advances in DNA recovery and sequencing have drastically expanded the scope of genetic analyses of ancient specimens to the extent that full genomic investigations are now feasible and are quickly becoming standard. This trend has important implications for infectious disease research because genomic data from ancient microbes may help to elucidate mechanisms of pathogen evolution and adaptation for emerging and re-emerging infections. Here we report a reconstructed ancient genome of Yersinia pestis at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348-1350. Genetic architecture and phylogenetic analysis indicate that the ancient organism is ancestral to most extant strains and sits very close to the ancestral node of all Y. pestis commonly associated with human infection. Temporal estimates suggest that the Black Death of 1347-1351 was the main historical event responsible for the introduction and widespread dissemination of the ancestor to all currently circulating Y. pestis strains pathogenic to humans, and further indicates that contemporary Y. pestis epidemics have their origins in the medieval era. Comparisons against modern genomes reveal no unique derived positions in the medieval organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions regarding emerging Y. pestis infections.

Lost in transition: influenza in the British army in the 1830s and 1840s.

This paper uses surgeons' reports from the 1830s and 1840s to investigate routine regimental medical care by focusing on a familiar, non-fatal disease. The regimental reports are used to describe the classification of influenza and the use of antiphlogistic regimen to treat the disease. Also discussed is how the surgeons reconciled the rapid spread of influenza with the predominant causation beliefs of the time. Furthermore, the patterns of influenza morbidity in the early middle 19th century are discussed, adding to the understanding of the historical epidemiology of this genetically variable virus.

Social contexts, syndemics, and infectious disease in northern Aboriginal populations.

Until the last half of the 20th century, infectious diseases dominated the health profile of northern North American Aboriginal communities. Research on the 1918 influenza pandemic exemplifies some of the ways in which the social context of European contact and ensuing economic developments affected the nature of infectious disease ecology as well as the frequency and severity of the problem. To understand these impacts it is necessary to consider the web of interactions among multiple pathogens, the biology of the human host, and the social environment in which people lived. At the very least, an understanding of the history of the impact of infectious diseases on northern North American communities requires attention not only to potential interactions among cocirculating pathogens, but their links to key social, historical, and economic factors that exacerbated their adverse effects and contributed to excess mortality.

Simulating the effect of quarantine on the spread of the 1918-19 flu in central Canada.

Quarantine is often proposed and sometimes used to control the spread of infectious diseases through a human population. Yet there is usually little or no information on the effectiveness of attempting to quarantine humans that is not of an anecdotal or conjectural nature. This paper describes how a compartmental model for the geographic spread of infectious diseases can be used to address the potential effectiveness of human quarantine. The model is applied to data from the historical record in central Canada around the time of the 1918-19 influenza epidemic. Information on the daily mobility patterns of individuals engaged in the fur trade throughout the region prior to, during, and immediately after the epidemic are used to determine whether rates of travel were affected by informal quarantine policies imposed by community leaders. The model is then used to assess the impact of observed differences in travel on the spread of the epidemic. Results show that when mobility rates are very low, as in this region, quarantine practices must be highly effective before they alter disease patterns significantly. Simulation results suggest, though, that effectiveness varies depending on when the limitation on travel between communities is implemented and how long it lasts, and that a policy of introducing quarantine at the earliest possible time may not always lead to the greatest reduction in cases of a disease.

Modeling the influence of settlement structure on the spread of influenza among communities.

Several factors play critical roles in the geographic spread of infectious diseases, including the movement of people between communities and the social and economic structure of groups of communities. A mathematical model has been developed to examine the individual and shared impact of these factors. This model was applied to the spread of the 1918-1919 influenza epidemic in three Aboriginal communities in central Canada. Previously published results from simulations of the model used parameter estimates for mobility patterns that were derived from historical documents from the study communities, especially Hudson's Bay Company post journals. We have termed this model the Frontier pattern. In this paper we extend that work to consider the consequences of three additional travel scenarios, which represent idealized trade and travel relationships between different communities. The three patterns include (a) the Central Marketplace scenario, an idealization of relations between a central community and its satellites in which a single central community satisfies all needs of the satellite communities; (b) the Sister Towns scenario, which allows travel among all communities and overemphasizes communication between satellites so that the ramifications of small town interactions are easier to observe; and (c) the Circuit scenario, which represents a hypothetical trade network that is a series of unidirectional dyad relationships linking all communities within a region. Results from simulations of the four mobility patterns are compared to assess the potential impact different social and economic relationships among communities may have had on the geographic spread of the 1918 influenza epidemic in central Canada and in other regions. These results reinforce conclusions that show that variation in patterns of mobility significantly influences the timing of epidemic peaks but only minimally alters the number of cases within a community. In addition, comparisons of the different models indicate that a central location in the social and political hierarchy of a region may be more important in influencing patterns of epidemic spread than just a central location with regard to travel patterns. Furthermore, who was actually travelling and where they were travelling had important consequences for epidemic spread. Am. J. Hum. Biol. 12:736-748, 2000. Copyright 2000 Wiley-Liss, Inc.