The Black Death, an outbreak of the bubonic plague which swept through Europe in the 14th century (killing anywhere from 30-60% of its population!), does not seem a good setting for a video game. Oh, unless it's Crusader Kings II we're talking about. Which, hey, we are.
The medieval murder/sex/papacy simulation is about to add disease management to its list of player options, with the upcoming release of The Reaper's Due, an expansion which introduces stuff like hospitals, proper epidemics which spread across sea and trade lanes (the game technically already has disease, including bubonic plague, but it was more of an "event" than something you could actually manage) and the option for your royal house to lock the castle gates and wait it out, which guarantees your survival but wipes out the countryside.
Here's my favourite addition, though: the chance for more story weirdness.
New Event Chains: Is the new epidemic the End of Days? Is there someone else to blame for these horrors? Are there supernatural origins or solutions to the world's problems?
Should be a hoot.