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Manchester City's clash with Everton on Monday night has been postponed after three more members of Pep Guardiola's first-team group tested positive for coronavirus.
It comes after Kyle Walker, Gabriel Jesus and two City staff members returned positive tests last week, missing the Boxing Day win over Newcastle.
City officials believe the outbreak has stemmed from a night's stay at a London hotel ahead of last week's Carabao Cup semi-final win over Arsenal.
Gabriel Jesus was among the Manchester City players to have previously tested positive
Kyle Walker is currently isolating and missed the Premier League game against Newcastle
The virus has now spread within City's bubble, meaning their game against high-flying Everton at Goodison Park will now no longer take place on Monday and Sunday's big fixture against Chelsea is also at risk.
City's first-team squad are due to be tested again on Tuesday.
The game had been scheduled to take place at 8:00pm so the postponement comes late in the day.
A Premier League statement read: 'Manchester City’s fixture at Everton, due to be played at 8pm this evening, has been postponed following a Premier League Board meeting.
'Manchester City lodged a request with the Premier League today to rearrange the game following an increase in positive COVID-19 test results received by the club this morning, on top of the cases reported on Christmas Day.
'This rise has created uncertainty and the Premier League Board received medical advice that the match should be postponed. The Board agreed to rearrange the game as a precaution, and further testing will now take place tomorrow.
Pep Guardiola's side will await the rescheduled fixture date and the Chelsea game is at risk
'The decision has been taken with the health of players and staff the priority.
'The Premier League continues to have full confidence in its protocols and rules, and the way in which all clubs are implementing them.
'The League wishes those with COVID-19 a safe and speedy recovery and will rearrange the postponed fixture against Everton in due course.'
Monday night's fixture was a highly anticipated encounter between City, rising up the table, and Everton, who have maintained a strong start to the season to sit in second spot behind Liverpool.
City beat Newcastle on Boxing Day without Jesus and Walker, who were isolating
Pep Guardiola's side are currently sixth in the Premier League table after 14 games
Jesus, Walker and the two staff members who previously tested positive have been in self-isolation since discovering they have Covid-19.
They have to remain quarantined for 10 days, per the government guidelines, as will the latest players to have contracted the illness.
City also released a statement, which read: 'After the latest round of Covid-19 testing, the club returned a number of positive cases, in addition to the four already reported on Christmas Day.
'With the security of the bubble compromised, there posed a risk that the virus could spread further amongst the squad, the staff and potentially beyond.
'Based on strong medical advice the Premier League, in consultation with both clubs, have decided to postpone the fixture.
Guardiola will be concerned about the health and fitness impact on his players
'All positive cases involving players and staff will observe a period of self-isolation in accordance with Premier League and UK Government protocol on quarantine.
'The first team training ground at City Football Academy will close for an indeterminate period, with the squad and associated bubble undergoing testing before any decision is made for training to resume.
'Everyone at the Club wishes all of our colleagues a speedy recovery ahead of their return to work, training and competition.'
The rearranged fixture will be a concern for Guardiola, given the number of games played already in the busy festive period.
And the manager will also be concerned about whether coronavirus impacts the health and fitness of the players who have caught it.
City are scheduled to face Manchester United in the Carabao Cup next Wednesday
City play Manchester United in the Carabao Cup semi-final next Wednesday but will be granted a postponement, if it comes to it, rather than have to forfeit the game as Leyton Orient had to with Tottenham earlier in the competition.
This is because the rules are different after the first four rounds where postponements can then apply.
The latest positive tests in the City squad could end up strengthening calls for a football 'circuit breaker' called for by the likes of Ipswich Town, who had seven staff members and five first-team players test positive for the new variant of Covid-19.
They were forced to postpone games against Northampton Town and Wimbledon, adding to the backlog of EFL fixtures.
Many at the club, including physio Matt Byard believe putting a stop to games for a period of time as a 'circuit breaker' could be an effective method of reducing the risk and more positive cases such as City's could add weight to that argument.