Isiekwe has now been ruled out of the first-round fixture in Rome on February 3rd, with his place in England's warm-weather training base in Girona, northern Spain, taken by fellow lock Charlie Ewels.

"Isiekwe .. has returned home because of illness. Ewels will arrive at England's training base in Girona later today," the RFU said in a statement.

Isiekwe was a possible bench option for the match with the Azzurri at the Stadio Olimpico and his absence has created another problem for England coach Steve Borthwick.

The biggest issue appears to be in midfield, with Ollie Lawrence ruled out until later in the Championship with a hip problem, and Oscar Beard sidelined with concussion.

As a result, either of the uncapped Fraser Dingwall or Max Ojomoh could now partner Henry Slade in the centres in what would represent yet another England midfield reshuffle.

Only Dingwall and Ojomoh have played regularly at inside centre, with Borthwick unable to call upon either Owen Farrell, after the former captain ruled himself out of the Six Nations on the grounds of mental well-being, or the injured Manu Tuilagi (groin).

Up front, Luke Cowan-Dickie has also been ruled out against Italy because of an unspecified medical condition, but the hooker could return for the second-round match against Wales at Twickenham.

Bath second row Ewels won the last of his 30 caps in the 2022 Six Nations and will be competing with Alex Coles to provide bench cover for Maro Itoje and Ollie Chessum.

England leave Girona for Rome on Thursday when Borthwick is set to name his starting XV.

Borthwick, himself a former England captain, has already announced that hooker Jamie George will succeed Farrell as skipper during the Six Nations.