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It happened around 12:30 a.m. on Irelan Drive near Singleton Street.
Firefighters rescued two people in the home and two others escaped on their own, said Chief Garland Johnston, of Western Wake Fire Rescue.
Stephen Lewardowski, 70, escaped injury. His wife, Karen Lewardowski, 67, was taken to the North Carolina Jaycee Burn Center at UNC in Chapel Hill.
One of the couple's sons, Mark Lewardowski, 42, was also taken to the burn center in Chapel Hill.
Another son, John Lewardowski, 43, was taken to WakeMed.
There were heavy flames when rescuers got to the home, Chief Johnston said.
The fire severely damaged the home. About 6:30 a.m., firefighters had to return to the scene after a hot spot flared up.
Sanaa Dali and her family live next door.
"It was horrific," Dali said. "There were flames everywhere. It was slowly consuming the entire house."
Dali said she tried to help Karen Lewardowski.
"When I got there, she told me that her son was trapped in his room and we both were trying to break the window," Dali said. "We were trying to break it with a chair but by the time we did break it we didn't hear any noise anymore."
Dali said that's when rescuers arrived.
Despite the risk she took, Dali said she's happy she was able to help.
"I'm doing fine," Dali said. "I just hope they're OK."
The Red Cross is helping the displaced family.
The cause of the blaze is under investigation.