We've got Republics, Aztecs, and Vikings, let's get something to do with the bubonic plague. There is a ton of stuff you could do with this that would give the player a lot of interesting choices.
For instance plague infested areas that are quarantined get a higher chance of revolting as more people in the city die, and sending an army there to deal with the revolt could spread more plague when the soldiers return to their own homes after fighting the peasants.
It could have a lot of interaction with the republic DLC as trading with plague cities increases the chances of getting plague.
Or an invading army from a plague city has a chance to spread plague to you.
You could send your court chaplain there to help stop the spread, it would potentially tear through the clergy that are stationed there. A bishop in a plague town might not last too long, but a town without a bishop is more likely to revolt.
It would also bring up a huge amount of dialogue options. Like building barricades etc. Also if an actual character gets infected perhaps you could have the option to lock them in quarantine at a relationship penalty if they survive. And the option to send characters you don't like to live in plague towns. Or to send your plague victims to other cities you don't like.
That's just stuff off the top of my head, but a plague DLC would add a whole lot of interesting options, and let you really get "stuck in" in that medieval age feeling. Right now the plagues that happen in the game don't have that apocalyptic feeling that they should.