Wayne Rooney and Tom Cleverley have joined Darren Bent in pulling out of Stuart Pearce's England squad for the friendly against Holland on Wednesday.
Gareth Barry is also a major doubt after a hamstring injury and a back spasm kept him out of Manchester City's 3-0 win over Blackburn.
Rooney has been suffering a throat infection that forced him out of Manchester United's 2-1 win over Norwich City as well as last Thursday's Europa League tie against Ajax. Cleverley has sustained an ankle injury and could be out for up to three weeks. "Very disappointed not to be joining up with the England squad tonight," said Cleverley on Twitter. "And again, it isn't a recurrence of the injury, it's the other leg."
Pearce must now re-evaluate his plans as he tries to balance playing an experimental side with making sure England are in a strong position to tackle the World Cup finalists. The caretaker manager would almost certainly have started with Rooney in attack but his illness, combined with Darren Bent's ankle injury sustained in Aston Villa's game at Wigan Athletic on Saturday, means a possible new-look strike partnership of the 22-year-old Daniel Sturridge and the 21-year-old Daniel Welbeck, with Fraizer Campbell in reserve.
Cleverley, earmarked by Pearce to win his first cap, now has only two international games at the end of the season, against Norway and Belgium, to gain some experience before the start of Euro 2012.
"They'll be out," Sir Alex Ferguson, the United manager, said of the two players. "Wayne has still not recovered from his throat infection, so hopefully we'll get him ready for next Sunday, when we have a big game [against Tottenham Hotspur]."
Rooney, who is banned for the first two games of Euro 2012, missed the friendlies against Spain and Sweden and Pearce was concerned about the striker not playing an international for the best part of a year.