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Prix de l'Arc de Triomphe favourite Danedream and British contender Nathaniel have been ruled out of Sunday's race at Longchamp but Epsom Derby winner Camelot should feature.
Defending champion Danedream was banned from travelling by vets.
The four-year-old German filly is trained at Cologne racecourse, which is under strict quarantine following the detection of a case of swamp fever.
Nathaniel was found to have a high temperature on Tuesday.
The horse, trained in Newmarket by John Gosden, had been second favourite behind Japan's recent Longchamp winner Orfevre after the withdrawal of Danedream.
News of his absence came just a few hours after the favourite was scratched from the race.
Although the Peter Schiergen-trained Danedream is not ill and in a different area to the sick horse, all equine movements from the German track have been halted due to the potentially-lethal nature of the disease.
Julian Pescatore, a spokesman for French racing's governing body France Galop, said: "There is a quarantine period of 90 days. For that reason, Danedream will not be able to run in the Arc.
"It is really sad that she will not be able to run, but there is nothing we can do about it."
“I'm using every profanity I know right now, plus a few I've invented”Julian Dollar, general manager of part-owners Newsells Park Stud, after Nathaniel was ruled out
A Cologne racecourse spokesman described the situation as "a nightmare". He added: "It is a disaster, especially as Danedream cannot take part in the Arc at the orders of the special vets."
Swamp fever is easily passed on and can cause mares to abort their foals as well as sudden death.
Nathaniel's setback was confirmed by James Wigan, racing manager to owner Lady Rothschild.
"He had a temperature this morning, they took some blood tests and his blood wasn't right," he said.
"Considering how close we are to the race, we cannot consider running him."
Those remaining in the Arc at the latest forfeit stage included 2,000 Guineas and Epsom Derby winner Camelot, who narrowly missed out on the Triple Crown when runner-up in the St Leger at Doncaster.
His trainer Aidan O'Brien has said he is "looking ahead very strongly" to the colt joining stablemate St Nicholas Abbey in the race.
However the absence of Danedream, this year's favourite, robs racing of the latest chapter in her remarkable story, one of the sport's great fairytales of recent years.
Purchased for just 9,000 Euros, she won major prizes at home in Germany and in Italy prior to her Arc success.
In July, the filly added Britain's King George VI and Queen Elizabeth Stakes to her tally.
Danedream and Nathaniel's absences are further blows to this year's Longchamp feature, European racing's great autumn championship, after Snow Fairy, third in 2011, was ruled out by injury.
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