Temperature Regulation and the Pathogenesis of Fever

The oldest known written reference to fever exists in Akkadian cuneiform inscriptions from the 6th century BC, most likely derived from an ancient Sumerian pictogram of a flaming brazier used to symbolize both fever and the local warmth of inflammation. Theoretical constructs of the pathogenesis of fever did not emerge until several centuries later, when hippocratic physicians proposed that body temperature, and physiologic harmony in general, involved a delicate balance between four corporal humors, blood, phlegm, black bile, and yellow bile. Fever was then believed to result from an excess of yellow bile, a concept in concert with the fact that many infections of that era caused both fever and jaundice. During the Middle Ages, demonic possession was added to the list of mechanisms thought to be responsible for fever. By the 18th century, Harvey’s discovery of the circulation of blood and the birth of clinical chemistry led iatrophysicists and iatrochemists to hypothesize alternatively that body heat and fever resulted from friction associated with the flow of blood through the vascular system and that they resulted from fermentation and putrefaction occurring in the blood and intestines. Ultimately, as a result of the work of Claude Bernard, the metabolic processes occurring within the body came to be recognized as the true source of body heat. Subsequent work established that body temperature is tightly controlled within a narrow range by mechanisms regulating the rate at which such heat is allowed to dissipate from the body.