Background: The impact of socio-demographic factors and baseline health on the mortality burden of seasonal\nand pandemic influenza remains debated. Here we analyzed the spatial-temporal mortality patterns of the 1918\ninfluenza pandemic in Spain, one of the countries of Europe that experienced the highest mortality burden.\nMethods: We analyzed monthly death rates from respiratory diseases and all-causes across 49 provinces of Spain,\nincluding the Canary and Balearic Islands, during the period January-1915 to June-1919. We estimated the\ninfluenza-related excess death rates and risk of death relative to baseline mortality by pandemic wave and province.\nWe then explored the association between pandemic excess mortality rates and health and socio-demographic\nfactors, which included population size and age structure, population density, infant mortality rates, baseline death\nrates, and urbanization.\nResults: Our analysis revealed high geographic heterogeneity in pandemic mortality impact. We identified 3\npandemic waves of varying timing and intensity covering the period from Jan-1918 to Jun-1919, with the highest\npandemic-related excess mortality rates occurring during the months of October-November 1918 across all Spanish\nprovinces. Cumulative excess mortality rates followed a southââ?¬â??north gradient after controlling for demographic factors,\nwith the North experiencing highest excess mortality rates. A model that included latitude, population density,\nand the proportion of children living in provinces explained about 40% of the geographic variability in cumulative\nexcess death rates during 1918ââ?¬â??19, but different factors explained mortality variation in each wave.\nConclusions: A substantial fraction of the variability in excess mortality rates across Spanish provinces remained\nunexplained, which suggests that other unidentified factors such as comorbidities, climate and background\nimmunity may have affected the 1918ââ?¬â??19 pandemic mortality rates. Further archeo-epidemiological research should\nconcentrate on identifying settings with combined availability of local historical mortality records and information\non the prevalence of underlying risk factors, or patient-level clinical data, to further clarify the drivers of 1918\npandemic influenza mortality.
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