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Fever is defined as a rectal temperature ≥38°C (100.4°F), and a value >40°C (104°F) is called hyperpyrexia . Traditionally, body temperature fluctuates in a defined normal range (36.6-37.9°C [97.9-100.2°F] rectally), so that the highest point is reached in early evening and the lowest point is reached in the morning. Any abnormal rise in body temperature should be considered a symptom of an underlying condition. The range of normal temperature is broad, 35.5-37.7°C (96-100°F); if 37°C (98.6°F) is considered normal, many cluster around this temperature (36.1-37.5°C [97-99.5°F]).
Pathogenesis
Body temperature is regulated by thermosensitive neurons located in the preoptic or anterior hypothalamus that respond to changes in blood temperature, as well as by cold and warm receptors located in skin and muscles. Thermoregulatory responses include redirecting blood to or from cutaneous vascular beds, increased or decreased sweating, regulation of extracellular fluid (ECF) volume by arginine vasopressin, and behavioral responses, such as seeking a warmer or cooler environmental temperature.
Three different mechanisms can produce fever: pyrogens, heat production exceeding heat loss, and defective heat loss. The 1st mechanism involves endogenous and exogenous pyrogens that raise the hypothalamic temperature set point. Endogenous pyrogens include the cytokines interleukin (IL)-1 and IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-β and IFN-γ. Stimulated leukocytes and other cells produce lipids that also serve as endogenous pyrogens. The best-studied lipid mediator is prostaglandin E 2, which attaches to the prostaglandin receptors in the hypothalamus to produce the new temperature set point. Along with infectious diseases and drugs, malignancy and inflammatory diseases can cause fever through the production of endogenous pyrogens. Some substances produced within the body are not pyrogens but are capable of stimulating endogenous pyrogens. Such substances include antigen-antibody complexes in the presence of complement, complement components, lymphocyte products, bile acids, and androgenic steroid metabolites. Exogenous pyrogens come from outside the body and consist of mainly infectious pathogens and drugs. Microbes, microbial toxins, or other products of microbes are the most common exogenous pyrogens, which stimulate macrophages and other cells to produce endogenous pyrogens. Endotoxin is one of the few substances that can directly affect thermoregulation in the hypothalamus as well as stimulate endogenous pyrogen release. Many drugs cause fever, and the mechanism for increasing body temperature varies with the class of drug. Drugs that are known to cause fever include vancomycin, amphotericin B, and allopurinol.
Heat production exceeding heat loss is the 2nd mechanism that leads to fever; examples include salicylate poisoning and malignant hyperthermia. Defective heat loss , the 3rd mechanism, may occur in children with ectodermal dysplasia or victims of severe heat exposure.
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