What is the mechanism by which fever occurs?

Mechanism of Fever

Fever occurs when exogenous pyrogens (infectious organisms or their products) or endogenous inflammatory mediators trigger immune cells to release pyrogenic cytokines (primarily interleukin-1 and interleukin-6), which then stimulate prostaglandin E2 synthesis in the anterior hypothalamus, resetting the thermoregulatory set-point upward and activating heat-generating mechanisms through the sympathetic nervous system. 1, 2

The Pyrogenic Cascade

The fever mechanism begins in the periphery when the immune system encounters a trigger 3, 4:

• Exogenous pyrogens (bacteria, viruses, toxins) or endogenous pyrogens (tissue damage, inflammation) activate immune cells in the blood and tissues 3, 2
• Activated immune cells release pyrogenic cytokines, particularly interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor, and interferon 1, 2
• This cytokine release is part of the acute phase response, a generalized reaction to infection or inflammation 1, 4

Signal Transmission to the Brain

Pyrogenic signals reach the central nervous system through two distinct pathways 3, 5:

Humoral Pathway (Primary Route)

• Pyrogenic cytokines from peripheral immune cells and liver travel through the bloodstream 3
• These signals access the brain via the circumventricular organ system (CVOS), which lies outside the blood-brain barrier 2
• The CVOS detects pyrogenic cytokines and initiates prostaglandin synthesis in the anterior hypothalamus 2

Neuronal Pathway (Alternative Route)

• Cytokines stimulate vagal sensory neurons in the periphery 3
• These neural signals transmit pyrogenic information indirectly to the hypothalamus 3, 5

Hypothalamic Reset and Temperature Elevation

Once pyrogenic signals reach the anterior hypothalamus 1, 5:

• Prostaglandin E2 (PGE2) is synthesized through cyclooxygenase-dependent pathways, serving as the neural mediator of fever 1, 2
• PGE2 acts on thermosensitive neurons in the anterior hypothalamus, which functions as the body's thermostat 1, 5
• The thermoregulatory set-point shifts upward to a higher temperature 1, 5
• Temperature thresholds for activating thermoregulatory effectors (cold thermogenesis, vasomotion, sweating) move to higher body temperatures 5

Heat Generation and Conservation

With the elevated set-point, the body activates heat-producing mechanisms through the sympathetic nervous system 1, 5:

• Vasoconstriction reduces heat loss through the skin 5
• Shivering thermogenesis generates heat through muscle activity 5
• Behavioral responses (seeking warmth, reducing activity) conserve energy 2
• These processes continue until core body temperature matches the new elevated set-point 1

Resolution Phase

Fever terminates when the pyrogenic stimulus resolves 5, 2:

• During later fever phases, the temperature threshold for cold thermogenesis moves downward while other thresholds remain elevated, creating an "interthreshold zone" 5
• This allows body cooling and fever termination 5
• The hypothalamic set-point resets downward as pyrogen content decreases or antipyretic therapy is administered 2
• Heat loss mechanisms (vasodilation, sweating) activate until temperature returns to normal 2

Pharmacological Interruption

Antipyretic drugs interrupt this mechanism at the prostaglandin synthesis step 1:

• Medications like acetaminophen and NSAIDs interfere with cyclooxygenase-dependent prostaglandin synthesis 1
• This prevents PGE2 from resetting the hypothalamic thermostat 1
• The set-point returns to normal, triggering heat loss mechanisms 2

Clinical Distinction: Fever vs. Hyperthermia

Critical pitfall: Fever differs fundamentally from hyperthermia 2:

• Fever involves a regulated upward shift in the hypothalamic set-point with intact thermoregulatory mechanisms 1, 2
• Hyperthermia (heat stroke, malignant hyperthermia, neuroleptic malignant syndrome) represents uncontrolled temperature elevation where thermoregulatory mechanisms are overwhelmed or dysfunctional 6, 2
• This distinction is crucial because antipyretics work for fever but are ineffective for hyperthermia, which requires external cooling 6