Fullback George Furbank has been ruled out of England's clash with South Africa at Ellis Park on Saturday and could miss the entire July tour because of appendicitis.
In a crushing blow to a player poised to make his first Test appearance since November 2024, Furbank was taken to hospital in Johannesburg on Friday after experiencing painful symptoms.
The 29-year-old fullback has been withdrawn from the side to face the Springboks and is unlikely to play any part in this month's additional Tests against Fiji and Argentina.
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Marcus Smith appears the most likely option to replace Northampton's Gallagher Prem title-winning captain given Freddie Steward has been struggling with an ankle problem.
Smith has been picked on the bench for the Nations Championship opener and any vacancy among the replacements could be filled by veteran Henry Slade.
England's chances of upsetting world champions South Africa have receded with the loss of Furbank, whose creativity provides a second ball playing option and valuable counter attacking threat.
It is also another setback for a gifted player who has been limited to 14 caps because of calf issues and a broken arm that was re-fractured.