I guess the question would be the intention of the author for what expansions would be used with it. I usually assume that each expansions is designed to play alone with the base set and may be added to any others. If we assume that it is played with the base set of 72 tiles and you include the 6 plague tiles, that is 78. Lets say for good measure that you add in the 5 King tiles and 10 non-river, GQ11 tiles (mine are not watermarked, so I don't seperate them), then you have 93. 17 of 93 tiles is a little over 18%, which for the sake of argument is about 1/5. So, if you're going to add a bunch of expansions, I'd say you increase that number by one for every six tiles you add.
Now, this is a general rule. I can see that not being too practical when playing with 300-400 tiles as following that formula would put you at upwards of 70 tiles. That might be a little too long to wait. I'd argue that you should not include the Wheel starting tile or the City in your count, but it would stand to reason that you should include the river since the plague can spread there without question. Do we have a ruling on spreading through the city?
Thank you for the response. Using a percentage seems to be a reasonable approach. However, after thinking about it, fleas running up the river wouldn't be much different than the Dragon doing the same thing if a Dragon tile was drawn shortly after the volcano/lake was placed. I intend to play with this a few times and report back with results.
As for The Plague spreading through the City, I haven't seen anything official, but I would assume The Plague would NOT spread through Carcassonne City. It seems like it would be immune for all the same reasons it is immune to attacks from the Dragon and Tower. I carry this over to the Wheel tiles as well, but that may get a little messy if a follower wants to flee to a portion of a city/road/field that is attached to the feature he's on, but located within these 'protected' tiles.