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Most children undergo at least one medical evaluation for a febrile illness before their third birthday, and nearly one third of pediatric outpatient visits are for fever. Fever is an increase in body temperature, usually by 1°C to 4°C, that is regulated by the central nervous system and mediated by endocrine, autonomic, and behavioral mechanisms. Although fever is a common manifestation of infection, it is a symptom of many diseases, both infectious and noninfectious.1-3


There is a normal diurnal variation that results in body temperatures that are approximately 0.5°C to 1°C higher in the late afternoon or early evening than in the early morning.2,3 Body temperature is controlled by the thermoregulatory center in the anterior hypothalamus, where thermosensitive neurons respond to changes in blood temperature and signals from cold and warm receptors in skin and muscle.2 Thermoregulatory mechanisms include the following:

  • Heat production by metabolic activity in the liver and muscles

  • Heat dissipation by the skin and lungs via redirection of blood flow to or from cutaneous vascular beds, sweating, tachypnea, and rigors (shivering)

  • Behavioral responses, such as seeking a cooler or warmer environment

Endogenous pyrogens, or cytokines, are small proteins that regulate immune, inflammatory, and hematopoietic processes and are important mediators of fever.2 The most studied of these are the primary endogenous pyrogens interleukin (IL)-l, IL-6, tumor necrosis factor-α, and interferon-α and -γ. These cytokines are released by leukocytes in response to infectious agents or toxic reactions. Peripheral cytokines, also called acute-phase reactants, are released in response to inflammation and use several mechanisms to signal the brain to produce fever. Once the cytokines are released into the bloodstream, they are carried to the hypothalamus, where they stimulate the vascular endothelial cell production of prostaglandin E2 (PGE2). Specific E-prostanoid receptors within the hypothalamus then trigger the febrile response after the PGE2 signal by resetting the hypothalamic temperature set point.1,2

Heat production exceeding heat loss is another mechanism that leads to an elevated temperature, which occurs, for example, in the setting of malignant hyperthermia and salicylate poisoning. Defective heat loss is the third mechanism that leads to an elevated temperature and can occur with exposure to severe heat or inability to dissipate heat, as seen in ectodermal dysplasia.2 Elevated temperatures due to these mechanisms are often referred to as fever, though the more accurate description is hyperthermia (see Definitions, below).

The diagnosis of fever is based on the measurement of core body temperature. Normal diurnal variations in temperature for an individual and normal differences in baseline temperature between individuals may be as much as 1.1 °C (2°F), but the generally accepted gold standard normal temperature is 37°C (98.6°F). Most clinicians consider any temperature above 38°C (100.4°F) to be a fever, especially in the immediate neonatal period. Beyond ...

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