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House and Cuddy board a flight back to the United States from Singapore, where they were speakers at an international conference. Shortly after takeoff, a passenger seated next to House becomes violently ill. While House brushes it off as a hangover, Cuddy suspects the man might have a deadly contagious virus and the other passengers could be at risk. Assuming the worst, Cuddy suggests the plane turn back and land, but House dissuades the flight attendant and the flight continues on. As the man's condition worsens, the rest of the passengers on the flight become increasingly uneasy, and so does House when a second passenger falls ill with the exact same rash and debilitating symptoms.
Back at Princeton-Plainsboro, Wilson leads the team when they encounter Fran, a middle-aged woman who collapsed at her home and soon goes into seizures. Cameron and Chase investigate Fran's house to look for clues to a diagnosis, but they are distracted by the prospect of an empty house and an inviting bed. When they return empty-handed and Fran's health continues to decline, the team must focus on finding out what is killing Fran without House's help. Back on the flight, with First Class turned into a makeshift isolation area, House calls upon a misfit team of passengers to fill in for his own team, as he bounces questions and theories off of them. When Cuddy collapses and several more passengers fall ill, the situation turns dire as the plane is hours away from any viable landing place. Without the help of his team or even proper medical equipment, House finds himself with Cuddys life and a plane-full of passengers lives in his hands.