In Davenport, Iowa, Pestilence is posing as a doctor at a convalescent home and visits an elderly patient, Celeste. He tells her that she’s suffering from three different diseases, and then gives her a fourth with a touch. When Celeste wonders what he’s doing, Pestilence explains that he’s using her to incubate a special disease and then watches as she vomits up her life.
One day earlier, Dean and Sam reunite with Bobby at the latter’s house. When Sam and Bobby explain Sam’s plan to let himself be possessed by Lucifer and take control long enough to trap him in the cage, Dean objects. Castiel calls them from a hospital and informs them that after his battle with the angels, he has lost his powers and ended up on a fishing boat. They wire money to him and Castiel apologizes to Dean for thinking he’s broken, burnt out shell of a man. Dean is duly appreciative.
Using the information provided by Brady, Dean and Sam track Pestilence to the convalescence home. They sneak in, knock out the security guard, and use the cameras to find Pestilence as he goes into Celeste’s room. They go after him, unaware that a demon nurse has spotted them. She warns Pestilence, but warns that he can’t harm the chosen vessels. Pestilence insists on avenging his fellow Horseman, holds her close to make her immune, and then uses his ring to infect everyone in the hospital with fatal diseases.
A weakened Sam and Dean manage to get to Celeste’s room, but Pestilence easily overwhelms them. He prepares to kill them slowly via disease, but Castiel staggers in. Pestilence easily strikes the non-powered angel down, but Castiel uses his last bit of power to resist long enough to cut off Pestilence’s ring finger, and then kill the demon nurse. Pestilence warns that it’s too long and his master plan is already under way, and then teleports out.
The trio goes back to Bobby, who tells them more bad news. A major storm is heading for Chicago, which will set off a chain reaction of disasters killing three million people. They figure it’s the work of Lucifer, using Death, and prepare to leave. However, they wonder how Bobby learned about the coming storm. When he prevaricates, Crowley appears and explained that he traded Bobby’s soul temporarily in return for a wish granting Death’s location. Dean demands that Crowley return Bobby’s soul, but the demon insists on holding it for insurance until they’ve defeated Lucifer.
When the group wonders what to do, Sam admits that he shares Dean’s concern that he’s too weak to contain Lucifer. However, they’re out of options. Crowley arrives and shows them a headline about Niveus’ distribution of the vaccine to combat the swine flu. He explains that Pestilence has grafted the Croatoan virus onto the vaccine, and is using Niveus’ nationwide distribution system and the high demand for the vaccine to spread it throughout the U.S. The group agrees to split forces. Sam, Castiel, and Bobby pack to stop the distribution of the
As they prepare to leave, Sam says that he agrees with Dean that he's too weak to take on Lucifer. However, he doesn't know what else to do. Crowley arrives to show them a newspaper article about Niveus Pharmaceutical distributing their new vaccine. They realize that the vaccine is filled with Croatoan virus and will be distributed nation-wide.
In Chicago, Death arrives in a pale car. When a man brushes past him and snaps, Death goes on his way as the man falls down, dead.
As Bobby and Castiel pack for their assault, Castiel complains about feeling useless now that he is merely human. Bobby notes he's in a wheelchair himself and doesn't have much sympathy. Crowley returns and gives them a rusty scythe which he says is Death's personal weapon of destruction. He explains that it can kill anything, even Death. He then wonders why Bobby isn't walking out with them. When Bobby points out that he can't walk, Crowley explains that he included a little extra in his wish. Bobby slowly stands up and realizes that he's healed. Crowley passes it off but Bobby gratefully thanks him.
As they drive to Niveus, Sam and Bobby tell Castiel about Sam's plan. To Sam's surprise, Castiel admits that the brothers have been capable of surprising him before, and that Sam might be able to resist Lucifer. However, he warns the others that Michael has decided to use Adam as his vessel, and that if Sam fails, Lucifer will use his body to set off the final Apocalypse in battle with Michael. He also explains that Sam will need near infinite power to contain Lucifer, requiring him to drink huge amounts of demon blood.
The trio gets to Niveus and watch as the first delivery truck leaves through the gate. They manage to stop it, knock out the driver, get inside, and begin their assault. The demon minions respond by unleashing the Croatoan virus on some of the human workers. They go berserk and attack Sam and Bobby, who have to shoot them down. They defeat the first wave of attackers and Sam tells Bobby to stay put while he coolly goes to rescue the remaining uninfected workers.
Crowley and Dean go to the warehouse that Bobby's wish has identified as Death's location. Reapers are lurking outside, but Crowley teleports in and discovers that the Horseman is no longer present. Insisting there's nothing else they can do, Crowley prepares to leave Chicago before the cataclysm strikes. He concedes that he'll have to give Bobby his soul back since the wish failed. They go back to the Impala but Crowley notices something at a restaurant nearby. He checks, confirms that Death is inside, and then teleports away.
Sam clears the building and saves the uninfected workers. One last Croatoan worker attacks and smashes him to the ground. Bobby tries to kill him but discovers he's out of bullets. Fortunately, Castiel arrives at the last minute and kills the possessed worker with a gunshot to the head.
Dean enters the pizza restaurant and discovers that everyone inside is dead. He spots the Horseman and prepares to attack him, but the scythe handle heats up, forcing Dean to drop it. Death teleports it to him and then invites Dean to sit with him and enjoy some Chicago-style pizza. When Dean wonders why he isn't dead, Death explains that Dean is no more than a bacterium to him, and dates back to the creation of the universe and beyond.
As Dean reluctantly eats, Death explains that he and God were among the first beings in Creation, and that eventually God will die at Death's hands. Dean wonders why Death wants him alive, and the Horseman explains that Lucifer has leashed him with a spell, and is using him to unleash cataclysms and start the Apocalypse. He wants Dean to defeat Lucifer and agrees to give him his ring. However, before he does he tells Dean that he must vow to stand aside and let Sam jump into the pit with Lucifer, since that's the only way they can win. Dean promises but Death warns him that if he's considering breaking his promise, he can't cheat death.
Later, Dean meets with Bobby and shows him how Death has shown him how to use them together. Bobby is happy to have his mobility back, but figures that if they don't win, he may not have long to enjoy his new legs. Dean wonders if he can cheat Death, but Bobby figures they are best off trusting in Sam to pull things off. He relates how Sam did everything that has ever been asked of him, and saved dozens of humans back at Niveus. Bobby insists that Sam will either defeat Lucifer, or die trying, and asks Dean if he's more worried about losing, or losing his brother.
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