Fever Revisited

¹ From The University of Michigan Medical School, Dept of Physiology, Ann Arbor, Michigan

It has been 12 years since I last wrote a Commentary on fever for Pediatrics.²⁹ As I pointed out in that review, fever, which occurs in response to infection or trauma, should be differentiated from "hyperthermia." During fever, the host behaves as if the temperature around which it is regulating (its thermoregulatory "set-point") were elevated. As such, during the rising phase of fever, the infected person will often shiver (increases heat production), will be peripherally vasoconstricted (a response that reduces heat loss), and will crawl under the covers or wear heavier clothing (behavioral responses that decrease heat loss). During hyperthermia, the core body temperature is above the thermoregulatory set-point, and the individual uses both physiological and behavioral means to lower body temperature. This is what happens as a result of exercising, particularly in a warm environment, or as a result of sitting in a sauna. When a fever "breaks" it is thought that the thermoregulatory set-point has returned toward normal, and it is at this time that the individual is hyperthermic. This is why the person will feel warm and will sweat during defervescence.

Since 1974 it has been known that fever has had a long phylogenetic history.⁶³ Fevers occur not only in infected birds and mammals, but also in infected reptiles, amphibians, fishes, and even insects (Table 1). The thermoregulatory set-point has risen in the infected "cold-blooded" organisms; and as a result, they behaviorally seek a warmer microclimate. Individuals who have tropical fish may have noticed that when their fish are sick, they tend to congregate near the light (or heat source). I suspect this is an attempt to get their body temperatures up to their raised thermoregulatory set-point.

WHAT CAUSES THE RISE IN THERMOREGULATORY SET-POINT?

Most evidence indicates that some stimulus (eg, bacterial endotoxin or viruses) causes the release of an endogenous pyrogen (EP), a small molecular weight protein, from macrophages. EP travels through the circulation to the brain, where in the anterior hypothalamus it causes a rise in set-point, presumably by causing an increase in prostaglandin E₂. Shortly after the first cytokines were identified, most investigators working in the area of temperature regulation and fever concluded that the cytokine, interleukin-1 (IL-1), was the circulating EP. IL-1, of which there are two forms: and , are thought to be responsible for numerous immune and nonimmune host-defense responses.

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