A fever, also known as pyrexia, is a controlled elevation of the body’s core temperature that occurs when the body’s internal thermostat is intentionally raised. This coordinated physiological response is typically triggered by infection or inflammation and is considered an adaptive part of the immune system. The body actively works to reach this new, higher temperature set point, which differentiates a fever from hyperthermia. Hyperthermia is an uncontrolled rise in body temperature that overwhelms the body’s ability to dissipate heat, without any change in the hypothalamic set point.
Pyrogens: The Chemical Signals That Start the Process
The initial trigger for a fever is specialized signaling molecules called pyrogens. These chemical messengers are categorized based on their origin. The process begins with exogenous pyrogens, which are substances originating from outside the body, primarily microbial components like the lipopolysaccharide (LPS) found in the cell walls of Gram-negative bacteria.
The presence of these foreign substances stimulates host immune cells, such as monocytes and macrophages, to produce endogenous pyrogens. These internal fever-inducing agents are cytokines, including Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-\(\alpha\)). These cytokines travel through the bloodstream to transmit the signal of infection or inflammation to the brain.
Resetting the Internal Thermostat
Once released, endogenous pyrogens travel to the hypothalamus, the brain’s thermoregulatory center. Since cytokines cannot easily cross the blood-brain barrier, they act upon specialized regions known as circumventricular organs. The organum vasculosum of the lamina terminalis (OVLT), near the preoptic area of the hypothalamus, is the primary site of this interaction.
In the OVLT, the binding of pyrogenic cytokines stimulates the production of an inflammatory lipid molecule called Prostaglandin E2 (PGE2). This synthesis is facilitated by the enzyme cyclooxygenase-2 (COX-2), which is the target of common fever-reducing medications. PGE2 mediates the febrile response and bypasses the blood-brain barrier issue.
PGE2 then diffuses into the adjacent preoptic area of the hypothalamus, which contains the neurons that regulate body temperature. It binds to the EP3 receptor on thermosensitive neurons. This binding effectively inhibits the neurons that normally work to keep the body temperature low.
By inhibiting the “cooling” neurons, PGE2 causes the hypothalamic set point to be rapidly elevated, much like turning up a home thermostat. The body’s regulatory mechanisms now perceive the current, normal temperature as too low compared to this new, higher target. The fever will persist as long as the concentration of PGE2 in the hypothalamus remains high.
The Body’s Heat Production and Conservation Methods
Following the hypothalamic set point elevation, the body initiates physiological responses to reach the new target. The first action is heat conservation, achieved through peripheral vasoconstriction. This process narrows the blood vessels in the skin and extremities, shunting warm blood away from the surface and toward the core.
This sudden reduction in blood flow leads to the sensation of feeling cold or having chills, even if the core temperature is already slightly elevated. The skin feels cool and appears pale because the body is actively trying to minimize heat loss. The chills signal that the body is operating as if it were in a cold environment, trying to meet the new, higher set point.
If heat conservation alone is insufficient, the body engages in active heat production. This is done through an increase in metabolic rate and involuntary muscle contractions known as shivering. Shivering is a highly effective way to generate heat, as the rapid, rhythmic muscle activity converts chemical energy into thermal energy.
These combined mechanisms continue until the body temperature successfully matches the new, elevated hypothalamic set point. Once the core temperature stabilizes at this higher level, the chills subside, and the feeling of coldness is replaced by the feeling of being hot.
Defervescence: The Return to Normal
The process of defervescence, or the breaking of the fever, begins when the underlying infection or inflammation starts to resolve. As the immune system gains control, the production of endogenous pyrogens (such as IL-1 and IL-6) decreases. This reduction leads to a corresponding drop in the synthesis of Prostaglandin E2.
With the concentration of PGE2 falling, its inhibitory effect on the hypothalamic thermosensitive neurons is removed, and the temperature set point rapidly returns to its normal baseline level. The body’s current elevated temperature is then perceived as too high relative to the new, lower set point.
To rapidly dissipate the excess heat, the body activates its cooling mechanisms. Vasodilation occurs, which is the widening of blood vessels in the skin, causing a flushed, warm appearance and allowing heat to be radiated away. This is followed by the activation of sweating, where the evaporation of moisture provides highly efficient cooling.