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2.09 Croatoan

In 2.09 Croatoan, following a vision of Sam's, they travel to River Grove, Oregon where people are overcome with amurderous with rage. A local doctor studies the blood of an infected person, noting that there appears to be traces of sulphur in the blood, leading Sam to further suspect demonic intervention. The virus is transmitted via exchanging blood, but the sulphur does not manifest in the blood until four hours after infection.

Sam speculates that it could be related to a theory in John's Journal, that Croatoan - a word they find carved into a telephone pole, is the name of a demon associated with plague and pestilence, and calls what's going on "demonic germ warfare".

Sam says, "I've been pawing through Dad's journal, I found something about the Roanoke Colony. Dad always had a theory about 'Croatoan'. He thought it was a demon's name, sometimes known as 'Deva', sometimes 'Resheph', a demon of plague and pestilence."

Sam is infected, but doesn't show any symptoms. Five hours later, the doctor announces that there is no trace of the virus in Sam's blood. All the remaining townsfolk have disappeared.

At the end Duane Tanner communicating presumably with Azazel via the Goblet of blood reports that "The Winchester boy is immune" (to the virus. Considering Sam's vision led them to River Grove, it's reasonable to assume that this 'demon virus' is linked in with the Yellow-Eyed Demon somehow.

5.04 The End

In 5.04 The End, an episode playing 5 years in the future of 2009, the Croatoan virus has broken out again. Past Dean reawakens in a Croatoan Outbreak zone, that is controlled by the military.