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The Plague aka The Black Death
The Bubonic Plague, aka Black Death first appeared in Italy in 1347 carried by fleas that infested rats that infested Spanish trade ships. It reached Germany, France, and England in 1348. 1/3 of England's population died, Florence, Italy lost between 1/3 and 2/3 of their population, and the fear of death prevented much travel to and from Europe. Urban conditions were so dirty that they were actually suited to help the spread of the disease. The only positives were higher per capita wealth and increased demand for social mobility.
The Pneumonic form of the disease infected people through direct interaction .