Ireland's hopes of beating England in their Autumn Nations Cup clash on Saturday suffered a significant double blow on Monday with captain Johnny Sexton and centre Robbie Henshaw both ruled out.
Sexton had hoped to be fit after going off in the first-half of the 32-9 victory over Wales on Friday but a scan ruled him out.
Sexton's absence could see Ulster's England-born flyhalf Billy Burns gain his first start at Twickenham after impressing when he replaced the 2018 World Player of the Year on Friday.
Burns also went off before the end of the match for a head injury assessment and will undergo the 'return to play' protocols this week.
Henshaw has an adductor strain and joins fellow Leinster centre Garry Ringrose on the sidelines, although Ireland have plenty of cover in that position.
"The Ireland captain Johnny Sexton has had a scan on the hamstring that forced his removal from the game on Friday night and has been ruled out of this week's fixture against England," read an Irish Rugby Football Union statement.
"Robbie Henshaw picked up an adductor strain and is also ruled out of this week's game."
There was more positive news regarding Burns's Ulster team-mates, full-back Jacob Stockdale and second-row forward Iain Henderson.
They were both late withdrawals from the starting line-up for the Welsh match.
"Jacob Stockdale will continue his calf rehab in camp with a view to training later in the week," read the statement.
"Iain Henderson will return to training today (Monday)."