The Newcastle fly-half will be out for four to six weeks after keyhole surgery on Friday in a Tyneside hospital and is now likely to miss England's autumn internationals against Australia, New Zealand and Samoa.
Wilkinson seemed to have recovered from the problem, which flared up on Newcastle's pre-season trip to Japan.
He played in the second half of the match at Sale but complained of being unwell again on Friday and he was operated on to remove the appendix.
He was released from hospital on Saturday and Newcastle director of rugby Rob Andrew said: "It's just the way things are.
"It's disappointing that we and Jonny have to go through all this again.
"It's starting to verge on the bizarre for Jonny. It's probably put paid to the autumn internationals for him and it's going to be two years since he played for England, and for us, for that matter.
"All Jonny's injuries and problems have been unrelated and he is getting to be very philosophical about things but in his position, what do you do? He has just got to get back on the horse and play and he'll be back, he'll be fine.
"The answer is to let him play before getting into picking him for England. Let's just let the bloke play and give him a chance to get back and then make a judgment."