The Spanish Influenza in Madrid: Excess Mortality by Age in Four - PDF document

The Spanish Influenza in Madrid: Excess Mortality by Age in Four Consecutive Waves Laura Cilek, Gerardo Chowell, Diego Ramiro Fari˜ nas ∗ 1 Background Contemporary estimations claim the influenza pandemic events between 1918 and 1921, the so-called ”Spanish” flu, accounts for the deaths of more than 50 million people throughout the world [1]. The series of successive influenza virus outbreaks gripped the world beginning in early 1918, however the initial circulation of the virus from avian or swine and other mammal species to humans, according to various phylogenetic and molecular-clock analyses, may have occurred as early as 1911 [2] or just before the first epidemic outbreaks in early 1918 [3]. Moreover, the symptoms and mortality patterns associated with this particular flu pandemic are particularly unique. For example, young-adults often exhibited the highest excess mortality rates, in contrast to seasonal influenza epidemics, which primarily affect the very young and elderly [4, 5]. The difference in age-specific influenza-related mortality by year and flu sub-type is often examined by using age specific mortality rates and calculating the risk ratio of mortality between two age groups of the proportion of excess deaths in a given age-group, as Simonsen et al calculate for influenza seasons between 1918 and 1989 [5]. While the location of the first human infection remains unclear, the virus likely moved to Spain via Spanish and Portuguese labor migrants in Southern France during the first world war [6]. The name ”Spanish” flu comes from the first reports of symptoms in Madrid in the late spring of 1918. However, the flu gained its moniker after mentions of the virus were first reported on and published in Spain, a neutral country in the war [7]. Nonetheless, in the spring and summer months of 1918, many concurrent herald outbreaks featured a strain that, while highly contagious, contributed to fewer overall excess deaths than the subsequent fall waves [8, 9]. In fact, the actual timeline and progression leading to the virus’s emergence is debated, though likely, the H1N1 strains responsible for the Spanish flu are related to those which caused the ”Russian” pandemic influenza events at the end of the 19th century and may have been present in both swine and humans more than 5 years before the first waves in 1918 [2]. While strains of the H1N1 virus continue to circulate in the form of seasonal influenza viruses, biological remnants of the particularly deadly 1918 strains are still found in avian species via the presence of specific encoded proteins [10]. In this manner, continued research into the unique aspects of the Spanish flu and its health and mortality impacts on the population are essential to understanding the potential effects that a virulent influenza strain could have on the global population today. 1.1 Age-Specific Mortality and Waves in the 1918 Influenza Epidemic Following a 1998 conference that focused on the pandemic, Johnson and Mueller undertook a effort to re-estimate global mortality from the pandemic using available studies and new techniques, proposing that the virus claimed the lives of at least 50 million [1]. While the pandemic events associated with the Spanish flu are perhaps most well-known for the aggregate mortality burden inflicted on the world, the unique age-specific mortality patterns of the successive outbreaks are also an extremely important trait of the virus. While excess mortality in seasonal influenza outbreaks nearly-unilaterally affects young children and those older than 65 (some longitudinal research using yearly cause- and age-specific death counts indicates additional, smaller influenza epidemics, such as in Canada in 1957, experience higher adult relative risk and mortality [11]), the epidemic waves beginning in the spring of 1918 uncharacteristically impacted young adults between the ages of 25 and 30 [12, 13]. Supporting evidence can be found in analyses employing a variety of methods and different types of data; for example, Viboud et al used individual death records in Kentucky from 1911-1919 to create a strong mortality baseline, then identified a peak mortality risk in ∗ laura.cilek@cchs.csic.es Center for Humanities and Social Sciences, Spanish National Research Council, Spain; Division of Epidemiology & Biostatis- tics, School of Public Health, Georgia State University 1

1918 (relative to the baseline years) for those aged between 24 and 26 [13]. Gagnon et al reviewed a slew of mortality data sources throughout the United States and Canada, including parish and civil registers, from September to December of 1918. Across these locations, they found peaks around age 28 in the percentage of deaths for both the percentage of deaths by age (across all ages, for pandemic-related causes) and for the percentage of all deaths (ages 15-44, all cause mortality) [12]. A few studies documenting excess age-specific mortality rates during the 1918-20 influenza pandemic reported little to no excess mortality for the elderly in the US and European settings [14], but an analysis of pandemic excess mortality rates revealed that seniors greater than 65 years of age experienced 1.5-2.4 fold higher excess mortality rates than young adults during autumn 1918 wave [15], corresponding to a 12-fold elevation over their baseline mortality rate. During the 1918 pandemic, in these cases of high excess mortality for both young adults and seniors, a true W-shaped pattern of excess mortality risk by age and a pattern occurs, where excess mortality rates peak in infants and young children, young adults, and the elderly population. Yet in the appearance of this w-shaped mortality curve varies by location and perhaps exposure to pre- vious strains of a familiar virus [16, 15]. Analyses conducted with census data and raw death counts during epidemic periods (with little to no baseline mortality information) reveal conflicting results as to a general mortality pattern by age; some evidence in rural and ”geographically isolated” populations show a w-shaped mortality pattern [17, 18, 19]. However, similarly completed analyses in other remote areas find instead a v-shaped mortality curve, in which the heighted mortality rates for adults does not decrease after the young-adult peak [14, 20, 15]. Other ”typical” w-shaped mortality curves can be found in non-remote urban and rural locations throughout the world (for example, a study in the United States measuring country-wide annual excess mortality determined from an yearly five-year baseline [16] or analyses in Copenhagen using nine years of weekly surveillance and mortality data [21]). Together, these continued excess morbidity and mortality analyses continue to foster the idea that a place or individual’s exposure to circulating H3 and H1 influenza strains contributed to their acquired immunity and played a role in mortality during the Spanish flu pandemic [15]. In addition to research using historical records, a review of the effects of pathogenic responses to strains of influenza virus hypothesizes that previous exposure to different circulating strains could have effected an individual’s mortality risk to the 1918 virus [22]. Depending on particular strain(s) of exposure, either some immunity may have been provided or the body many have triggered an incorrect pathogenic response, explaining high flu- related mortality from subsequent respiratory infections [22]. These findings suggest substantial differences between countries in prior immunity to the 1918 influenza A(H1N1) virus. Both systematic reviews of seasonal and pandemic virus circulation [8] and mortality analyses that focus on the timing of each wave, as in a 2010 paper examining the 1918 influenza impact in Mexico [23], show such differences could result from a heterogeneous circulation of influenza viruses in the 19th century. The Reproduction number ( R ) is another key estimation often included in influenza epidemiology anal- yses to analyze the transmissibility of a disease in a given population. Most simply, R can be interpreted in terms of the demographic measurement of the Net Reproduction Rate; thus, the Reproduction number can be considered as the number of secondary cases (of influenza) that each infected individual (primary case) produces. Similar to its demographic equivalent, R also depends on the length of time required to generate the disease, or the mean length of time the virus is present in an individual [24]. If the value of R equals 1, the size of the epidemic remains the same or reaches unity, and if the number becomes lower than 1, the number of cases of disease will decrease. However, an R value greater than one implies that an epidemic grows, and the larger the number is, the higher the likelihood that interventions will be more difficult to implement and the growth of the disease difficult to control. Estimates of the Reproduction number for pandemic events tend to be higher than those of seasonal influenza; a comprehensive review of published R estimates (calculated by various methods) by Biggerstaff et al found the mean R value of the 1918 and 1968 influenza outbreaks was 1.80, but seasonal influenza estimates for R were often lower, with a mean published value of 1.28 [25]. Chowell’s 2009 chapter on the calculation of R found more than 11 published estimates of R for the 1918 epidemic with values ranging from 1.4 to 5.4 [24], though he also notes that differences in location and size, demographic composition, and which wave(s) were considered, as well as the technique used to calculate the number, can affect the estimated value of R . In general, the timeline of the pandemic is broadly classified into three different wavesa short but intense 2