The 25-year-old lock will now miss the first-round fixture in Rome on February 3, with his place in England's warm-weather training base in Girona, northern Spain, being taken by fellow lock Charlie Ewels.
"Isiekwe...has returned home due to illness. Ewels will join England's training base in Girona later today," the RFU stated in a press release.
Isiekwe was a potential option for the bench in the match against Italy at Stadio Olimpico, and his absence poses another challenge for England coach Steve Borthwick.
The main concern seems to be in the midfield, with Ollie Lawrence sidelined until later in the Championship due to a hip problem, and Oscar Beard out with concussion.
As a result, either the uncapped Fraser Dingwall or Max Ojomoh could potentially partner Henry Slade in the centers, leading to yet another reshuffle in England's midfield.
Dingwall and Ojomoh are the only options with experience at inside center, as Borthwick is unable to call upon Owen Farrell, who has opted out of the Six Nations for mental wellbeing reasons, or the injured Manu Tuilagi (groin).
On the forward front, Luke Cowan-Dickie is also ruled out of the Italy match due to an unspecified medical condition, but the hooker could make a return for the second-round clash against Wales at Twickenham.
Bath's Ewels, who has 30 caps to his name, last represented England in the 2022 Six Nations. He will be competing with Alex Coles for the role of providing bench cover for Maro Itoje and Ollie Chessum.
England is set to leave Girona for Rome on Thursday when Borthwick is expected to announce the starting XV.
Borthwick, a former England captain himself, has already revealed that hooker Jamie George will take over the captaincy from Farrell during the Six Nations.