The bug has already decimated the under-21 set-up, and although the club believed they had contained it, three senior players in Asmir Begovic, Geoff Cameron and Phil Bardsley have now been laid low.
Hughes is hopeful the illness will pass in 24 hours and the trio will be in training again on Friday, but has no idea who might be the next victims ahead of Saturday's Barclays Premier League trip to Liverpool.
Hughes explained: "We're struggling to contain it somewhat.
"The under-21s were hit by it earlier in the week
We tried to deal with it there and then.
"We closed their operation down to such an extent they haven't been in or around the building for the last three days, and they won't be in tomorrow either.
"Unfortunately, today Asmir, Geoff and Phil reported they were feeling unwell with sickness and what have you.
"Phil came in and was prepared to train, but under the circumstances we felt he was better served by returning home.
"Asmir was ill overnight and didn't report in, and Geoff was sick when he came into the building, so he went straight back."
Asked as to the cause, Hughes replied: "It could be the time of the year, something that's around, that you pick up from your kids.
"We're not sure where it's come from
We tried to sanitise the building on Wednesday, we went right through it.
"Hopefully it's going to be a 24-hour thing and they'll be okay, but naturally it's something we're having to monitor.
"We thought we'd got hold of it, but after this morning we've had to put those thoughts on the backburner.
"We're trying to keep the impact of it to a minimum if we can, but we're at the mercy of it
We're hoping nobody else will go down with it.
"In 24 hours' time we might be in a similar situation with different people, but we're hopeful we've done enough."
For Hughes, it is a case of illness being added to injury given the number of players who have been on the sidelines of late.
On-loan Victor Moses joined the list on Wednesday as he will be out for six-to-eight weeks with a thigh injury.
Better news for Hughes, though, is that defenders Erik Pieters and Marc Wilson returned to training this week after missing the 2-1 home defeat to Burnley last Saturday with calf and hamstring problems respectively.
Crucially, influential centre-back Robert Huth is on the brink of a return after a recent calf injury.
Huth has not played a league game for a year after sustaining a long-term knee injury, and although fit in pre-season, has only played two Capital One Cup matches this term due to setbacks.
Hughes added: "He's doing really well
He's very close to joining in with the senior squad again, which we are all delighted about.
"We're coming into a period of games in a short period of time, so we are going to need bodies, and Rob coming back at this time of year is a bonus for us.
Source : PA
Source: PA