Pep Guardiola has tested positive for Covid-19 as seven first team players and 14 backrooms staff are forced to self-isolate.
Guardiola recorded a positive test on Tuesday along with assistant Juanma Lillo and are both self-isolating.
The Premier League champions have confirmed 21 members of the first team bubble have tested positive.
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City play League Two club Swindon Town in the third round of the FA Cup on Friday. Assistant coach Rodolfo Borrell will take charge of the team for the trip to Swindon.
Despite their Covid-19 outbreak, Borrell insists the team are mentally prepared to take to the field, albeit with limited options to choose from.
"At the end of the day, it's possibly going to be one of most easy line-ups we have had to decide because we're just going to play with the one that we have available," he said.
"We don't have much more. Our aim is to keep playing as much as we can, trying to respect all competitions.
"At this moment we can field a team. I don't know in the following days what is going to happen, but right now it's an easy decision to decide the line-up because we will play with what we've got.
"We have some first team players, and some others that are going to come from our second team."
Elsewhere, Burnley boss Sean Dyche will also miss his side's cup tie against Huddersfield Town on Saturday afternoon after testing positive for Covid-19.
The Premier League club said: “Burnley Football Club can confirm manager Sean Dyche will miss this weekend’s FA Cup third-round tie at home to Huddersfield, after testing positive for Covid-19 on Tuesday. Sean will now follow the mandatory self-isolation protocols.”
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