Alexander witnessed ravens dying in Babylon before he became ill. Credit: © GettyImages

He ruled Macedonia, crushed the Persian Empire and invaded India. But a simple infection with West Nile virus may finally have toppled Alexander the Great.

The legendary military leader died suddenly in 323 BC in the Mesopotamian city of Babylon, near current-day Baghdad. The cause of his death, aged only 32, has puzzled historians for years. Poisoning, flu and typhoid fever have all been suggested, based on records of his two-week illness.

Now epidemiologist John Marr of the Virginia Department of Health in Richmond and infectious-disease expert Charles Calisher of Colorado State University in Fort Collins have a new suggestion: West Nile fever1.

Common in Africa, West Asia and the Middle East, West Nile virus has found renewed global fame since its accidental introduction to the United States in 1999. The virus is harboured by birds and other animals and is transmitted to humans by mosquitoes.

Marr and Calisher cite a passage by the Greek biographer Plutarch. "When [Alexander] arrived before the walls of [Babylon]," Plutarch recorded, "he saw a large number of ravens flying about and pecking one another, and some of them fell dead in front of him."

The ravens might have been dying of West Nile virus infection, the researchers suggest. Ravens belong to a family of birds that are particularly susceptible to the pathogen - members of the same family are responsible for the virus' spread across the United States.

Marr and Calisher tested their idea using an online diagnostic program called GIDEON (Global Infectious Diseases and Epidemiology Network). After entering Alexander's symptoms - respiratory infection, liver disorder, rash - plus the link with birds, "the answer was West Nile, 100%", says Calisher.

"It's fairly compelling," says Thomas Mather, an epidemiologist at the University of Rhode Island in Kingston. But West Nile virus tends to kill the elderly or those with weakened immune systems, he points out. "If he was so great, he might not have been bumped off by this disease," Mather says.

Case history

Alexander the Great - more properly known as Alexander III of Macedon - quashed enemies in his own kingdom before famously conquering the Persian territories of Asia Minor, Syria and Egypt. He eventually built an empire that stretched west as far as Greece, east to India, and north to the Danube.

If he was so great, he might not have been bumped off by this disease Thomas Mather , University of Rhode Island

Calisher admits that Alexander's retrospective diagnosis cannot be certain. But he says that the study illustrates how important it is for doctors today to take into account the full history of a case - such as exposure to animals.