Bob Kravitz of the Indianapolis Star reported Pagano would miss several games due to a "serious" illness.
Pagano had been feeling unusual fatigue in recent weeks and got blood tests during the bye week.
The Colts will have a press conference this morning, at which time they will introduce Pagano's doctor and offer more specifics on his illness.
One top organization official acknowledged it's serious, but added "we're very optimistic about his recovery."
Offensive coordinator Bruce Arians will take over as the team's head coach for this week's game against Green Bay. Pagano hired Arians during the offseason to help develop rookie quarterback Andrew Luck.
The Star recently profiled the "intense" Pagano and the importance his family plays in his professional life.