Abstract

Just over a century ago in 1918–1919, the “Spanish” influenza pandemic appeared nearly simultaneously around the world and caused extraordinary mortality—estimated at 50–100 million fatalities—associated with unexpected clinical and epidemiological features. The pandemic's sudden appearance and high fatality rate were unprecedented, and 100 years later still serve as a stark reminder of the continual threat influenza poses. Sequencing and reconstruction of the 1918 virus have allowed scientists to answer many questions about its origin and pathogenicity, although many questions remain. Several of the unusual features of the 1918–1919 pandemic, including age-specific mortality patterns and the high frequency of severe pneumonias, are still not fully understood. The 1918 pandemic virus initiated a pandemic era still ongoing. The descendants of the 1918 virus remain today as annually circulating and evolving influenza viruses causing significant mortality each year. This review summarizes key findings and unanswered questions about this deadliest of human events.