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A lack of data up until 1500 AC complicates the research on influenza before that period<ref name="Arti8">Internet‐Based Intelligence in Public Health Emergencies, NATO Science for Peace and Security Series - E: Human and Societal Dynamics, 2013 Mordini E., Green M., https://www.iospress.nl/book/internet%E2%80%90based-intelligence-in-public-health-emergencies/</ref>. Possibly the first influenza pandemic occurred around 6000 BC in China. The symptoms of human influenza seem to have been clearly described by Hippocrates, roughly 2,400 years ago<ref name="Arti9">2,500-year Evolution of the Term Epidemic, Emerging infectious diseases, 2006, Martin PM, Martin-Granel E, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373038/</ref>. Although the virus seems to have caused epidemics throughout human history, historical data on influenza is difficult to interpret, due to the fact that symptoms of influenza are similar to those found in other respiratory diseases, like RSV (respiratory syncytial virus).
The most infamous and lethal outbreak was the 1918 flu pandemic (Spanish flu) (type A influenza, H1N1 subtype), which lasted into 1920. The number of deaths is unknown, but estimates range from 17 to 100 million people<ref name="Arti10">Reassessing the Global Mortality Burden of the 1918 Influenza Pandemic, American journal of epidemiology, 2018, Spreeuwenberg P, Kroneman M, Paget J, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314216/</ref>. This pandemic has been described as "the greatest medical holocaust in history" <ref name="Arti11">Reviewing the History of Pandemic Influenza: Understanding Patterns of Emergence and Transmission, Pathogens, 2016, Saunders-Hastings PR, Krewski D, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198166/</ref> and may have killed as many people as the plague (Black Death). This huge death toll was caused by an extremely high infection rate of up to 50% and the severity of the symptoms, suspected to be caused by cytokine storms in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines.
One of the most recent outbreaks of influenza was the 2009 Swine Flu. Similar to the Spanish Flu, it was also of the subtype H1N1. The death toll of the 2009 pandemic is estimated to be around 150,000 to 575,000.
