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Some analysis has been done on the sequence of 1918 influenza strains. It is thought that it was a H1N1 strain of influenza A, known also as "swine flu". It is thought that the virus was particularly virulent due to a mutant strain of the hemagglutinin (HA) surface protein it carried. For activation, HA must be cleaved by a host protease. The normal protease responsible is found in the respiratory tract of humans, or the digestive tract of avians. Some mutants of avian flu contain different sequences at the cleavage point, allowing them to be cut by a wide variety of proteases, allowing the virus to be activated anywhere in the body. It is not known for certain that this is responsible for the virulence of the 1918 strain.

The most popular speculation for why the "Spanish Flu" seemed to kill the most healthy individuals is that the immune response itself was responsible for the pneumonia that killed many. A stronger immune response, like that of an adult in their 20s, would result in more rapid secretion of mucus in the lungs, causing the victim to essentially drown in it.