Basically, I'm trying to homebrew a tough disease. Something players could get under control in their group, but it's too big and too virulent to be stopped easily in an entire city.

The Plague

One of the major obstacles of City of Death is a disease just known as The Plague.

*Note, these rules assume you are using the OneD&D playtest. If you are using the original exhaustion mechanics, treat the exhaustion levels as “half-levels”

When infected with the plague, the victim starts at stage 1. At the end of a long rest, the victim must make another Constitution Saving Throw (DC 15) or get worse by 1 stage. A success by 5 or more lowers the stage disease by 1. If someone was treating the victim for at least 4 hours in the prior day, that person can make a Wisdom (Medicine) check, with a penalty for the stage of the disease. The victim can use the check in place of their Constitution Saving throw.

Stage 1 weakens its victim with a level in exhaustion. Each stage beyond, in addition to another level in exhaustion, also randomly infects one ability score of the victim. Any d20 Test with the infected ability score is made with disadvantage. Any saving throw against a DC determined by an infected ability score is made with advantage. Each stage infects an ability score out of the uninfected scores at random.

At stage 8, when the disease has infected all of the ability scores, it starts to set in worse. The victim takes two levels of exhaustion for each stage starting at 8. Most will die at stage 9, after taking 11 levels of exhaustion.

No levels of exhaustion caused by The Plague can be recovered unless the stage of the disease is lowered.

Treatment:

The plague is tough to heal. Every stage of the disease acts like a new disease. Additionally, the disease is resistant to magic. If someone uses an ability that cures a disease, they must make a Spellcasting Ability Check (DC 15) or The Plague does not regress. If the effect cures all diseases, make the check for each stage of the Plague. The disease regresses one stage for each success.

The Plague can also strike at those immune to disease, though immunity to regular disease does grant advantage to the Constitution Saving throw. Also, if both dice would result in beating the DC by 5, the plague regresses two stages instead of one.

Containment:

While quarantine could shift the tide against the disease, Dr. Kurtis Clark, one of the lords of the city, says the cure is so close that quarantine could do more damage than it fixes. Other lords, like Chief Caden Holzmann and the honorable Marianne Dewan, have lent their support to Clark’s actions.