It sounds too implausible to be true: Alexander the Great, king of Macedon and conqueror of the Persian Empire, undefeated in battle and considered one of history's most successful commanders — defeated by the bite of a mosquito infected with West Nile virus. What!?


West Nile virus has only emerged as a public health threat in America and Europe in the last decade. The mosquito-borne virus was first isolated from a febrile patient in Uganda in 1937, and the first true outbreak of West Nile encephalitis in humans was recognized in Algeria in 1994, only 18 years ago. So isn’t this virus more of a contemporary concern?


It would seem so, but a historic review paper published in 2003 in Emerging Infectious Disease, and lingering in the Centers for Disease Control and Prevention’s electronic archives presents a compelling argument that infection with the West Nile virus might have been the culprit in Alexander’s death.


Born in Pella in 356 BC, Alexander had created one of the largest empires of the ancient world by the time he turned 30. Following a two-week febrile illness, he died at the age of 33.


There has been intense speculation about the cause of his death. Theories have run the gamut from poisoning to contraction of a number of infectious diseases. The authors of the paper methodically pick these theories apart.


People most commonly believe that poison was the cause of his demise. One of the key symptoms Alexander suffered from was fever, yet few poisons induce fever, and the few that do were not available in Alexander's time. In Plutarch’s writing there is mention of Aristotle (Alexander’s tutor) obtaining arsenic to poison Alexander, but arsenic is not likely to have killed Alexander since it would not have caused the high, sustained fever that was reported.


Were there other infectious diseases at play? Diseases endemic to the area — such as leishmaniasis, bubonic plague and hemorrhagic fevers — were not noted by those who described Alexander’s death. In addition, illness among his troops was not reported. Chronicles of Alexander’s illness also do not include common signs of disease like rash, icterus, thin blood, vomiting, diarrhea, dysentery, hematuria or seizures. The authors go on to rule out malaria, typhoid fever, Schistosoma haematobium infection, influenza, poliomyelitis and Guillain-Barré syndrome. 


So how does West Nile play into this historical mystery?


While West Nile virus wasn’t isolated in a human until the 20th century, infections in vertebrates may have been occurring in the Middle East for centuries. And Alexander's symptoms are consistent with those of West Nile. But the potential smoking gun can be found in the writing of Plutarch. The historian mentions that as Alexander entered Babylon, a flock of ravens exhibited unusual behavior and subsequently fell to the ground:


When he arrived before the walls of the city he saw a large number of ravens flying about and pecking one another, and some of them fell dead in front of him.

The mysterious behavior of ravens brings to mind the erratic birds and avian illness and deaths reported before the first human cases of West Nile virus infection were identified in the United States.


If this observation is included as part of Alexander’s illness, West Nile virus encephalitis complicated by flaccid paralysis becomes a viable diagnosis. It is possible, say the authors, that in the third century B.C., disease caused by West Nile virus arrived in Mesopotamia for the first time in recorded history, killing indigenous birds and an occasional human and causing only incidental febrile illness in many others. Over subsequent centuries the virus may have devolved, becoming less pathogenic for indigenous birds, while retaining its potential as a dangerous human pathogen.


Perhaps the history books should finally acquit Aristotle?


More West Nile and disease stories on MNN: