The Wasps full-back, an ever-present under head coach Andy Robinson, damaged his left shoulder in the first minute of England's 47-13 victory over Wales at Twickenham.
Lewsey soldiered on for 20 minutes but finally conceded defeat when he could no longer lift his arm.
The England camp were relieved that a scan on his ACL joint - which connects the collar bone to the shoulder - showed no evidence of structural damage.
Leicester winger Tom Varndell, fresh from scoring four tries for England A last weekend, has been drafted into the 31-man squad as Lewsey's replacement.
Bristol scrum-half Shaun Perry has also been called up, in place of Gloucester's Peter Richards who also has a shoulder injury.
Winger Mark Cueto suffered bruising to his lower back, but is available to Robinson, who names his side to play Italy on Tuesday afternoon.
Tom Voyce, Lewsey's Wasps colleague, impressed Robinson with a try-scoring performance off the bench on Saturday and could now make his first Six Nations start for England.
But England are unlikely to make many other changes for the trip to Rome, where they face an Italian side who gave Ireland quite a scare at Lansdowne Road.
The loss of Lewsey, who could be out for at least a fortnight, leaves England short of cover in the centre, possibly opening the door for Stuart Abbott to win a place on the bench.
Otherwise, Robinson wants to keep his side together and build on a performance against Wales that Lewsey described as England's best since the World Cup.
"Apart from the injury we've got with Josh, I'm not really going to make any changes," said Robinson.
"We must focus on beating Italy because everything will be wasted if we don't put another big performance in. Rome is a tough place to go and Italy are always hard to play against.
"What was pleasing against Wales was the finishing of Mark Cueto for the first try, the superb Mike Tindall try that involved everybody and also the last try from Tom Voyce which went through a number of phases.
"That was the way we wanted to play. We wanted to move the Welsh forwards around. We knew that the Welsh liked to attack but didn't like to defend so if we moved the ball around spaces would open up.
"I thought Charlie Hodgson had an immense game and Harry Ellis played very well. I think the centre combination is finding their feet together.
"It's important to build on that performance again."
Robinson felt a certain sympathy for Pierre Berbizier, who is enjoying his first Six Nations in charge, after the narrow defeat to Ireland but that will go out the window on Saturday.
"I'm disappointed for the Italians," said Robinson.
"They missed a number of penalties against Scotland last year which could have given them a famous win at Murrayfield.
"I thought they played really well against Ireland and we know there's going to be a real storm hitting us at the Stadio Flamino for the first 20 minutes.
"They have very strong forwards. Pierre Berbizier looks as if he's bringing a back line together who can perform as well.
"Whatever ball we do get we've got to use it properly and we've got to take our opportunities like we did last Saturday.
"I'm looking forward to that challenge. I think it will be a great game and all the Italian sides are getting better and better. All credit to them."