The coronavirus and injuries are creating a hole in the centre of the Italy national team as it prepares for the start of 2022 FIFA World Cup qualifying.
Chelsea midfielder Jorginho and Inter Milan counterpart Nicolo Barella have been regular starters under Italy coach Roberto Mancini.
But the former has a knee injury and the latter has still not been able to join up with the national squad because of coronavirus restrictions.
Inter duo Stefano Sensi and Alessandro Bastoni are also subject to those restrictions, while Roma midfielder Bryan Cristante was called up but has an injury.
"As regards to the midfielders, we are really in a bit of difficulty in the centre," Mancini said on Tuesday.
"We're missing Jorginho, who wasn't well, he'd taken a knock to the knee and he wasn't fit to play in these games so we didn't risk him.
"Bryan Cristante will probably go back home. We'll wait and see what happens with the Inter lads."
Inter's Serie A match against Sassuolo on Saturday was postponed because of coronavirus cases in the squad. Its players were also banned from travelling for international duty.
Team activities were allowed to resume on Monday and several of Inter's international players returned to their home countries, where they will be permitted to train but not travel to a third country or play matches until March 31.
However, the Italian Inter players have to wait for special dispensation to join their teammates at national team headquarters in Coverciano.
"I'm disappointed not to have them with us but we are fairly confident (they can join up)," Mancini said.
The Azzurri kick off their World Cup qualifying campaign at home to Northern Ireland in Parma on Thursday. They play Bulgaria away on March 28, and Lithuania away three days later.
"The first match will certainly be a bit more difficult because it is the first one after five months," Mancini said.
"We're facing a team which isn't so easy to play against ... all the players play in the Premier League.
"But you can't make any mistakes in World Cup qualifiers. We will have to try to give our all in the next three games."