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I'm aware that Cash made a thread very much like this one, but I don't know what the policy on necro-ing old threads are, so I'll make another one.
As we're all aware, a cocktail of diseases devastated the American continent after contact between Europeans and Americans. What if there were also native diseases to which the Europeans didn't have as strong an immunity? Say that by the end of the 16th century, 80% of European colonisers have have set foot on the continent are dead. How would history have changed with such a high mortality rate?
What if the diseases crossed the Atlantic and struck Europe?