The crash took place near Grand Avenue in the northbound lanes in Streeterville, Chicago fire officials said.
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Two children were taken to Lurie Children's Hospital with minor injuries in good condition, officials said.
The driver suffered a medical emergency before losing control of the bus, Chicago police said. He later died at a hospital.
He was identified as 39-year-old Christopher Johnson by the Cook County Medical Examiner's Office. His exact cause of death was not immediately known.
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Traffic was slowly getting around the crash just before 4 p.m.
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