Ben Youngs has been ruled out for the rest of England's Six Nations campaign and faces four months on the sidelines after rupturing ligaments in his left knee.
England successfully began their bid for a record third straight outright Six Nations title with a 46-15 win over Italy in Rome on Sunday, but lost Youngs to injury less than 10 minutes into the game.
The scrum-half went down after his left leg appeared to get trapped in a ruck. He had several minutes of treatment on the pitch before being taken off on a stretcher.
The Rugby Football Union revealed in a statement on Monday that the Leicester half-back has "ruptured his MCL in his left knee and is having further assessment with a surgeon this week".
England have called up Richard Wigglesworth as Youngs' replacement for Saturday's game against Wales at Twickenham.
Wigglesworth, who has 27 international caps, has played at two Rugby World Cups in 2011 and 2015 and was last called up to the squad in May 2017.
The 34-year-old has made over 180 appearances for club side Saracens, where he has won Premiership and Champions Cup titles.
Danny Care is expected to start in the number nine jersey against Wales at Twickenham, having stepped off the bench to replace Youngs at the weekend.