An elevation of core body temperature above normal range (>38°C/100.4°F), triggered by inflammatory mediators acting on the hypothalamic thermoregulatory center. Fever is an adaptive immune defense mechanism, not a malfunction, that enhances immune function and inhibits pathogen replication.
PAMPs/DAMPs activate immune cells (macrophages, dendritic cells) to release pyrogenic cytokines (IL-1β, IL-6, TNF). These cytokines act on circumventricular organs (OVLT, organum vasculosum of lamina terminalis) lacking blood-brain barrier, triggering COX-2 production of PGE2. PGE2 acts on EP3 receptors in preoptic area of hypothalamus, raising temperature set-point. Hypothalamus initiates heat conservation (vasoconstriction, shivering) and production (increased metabolism). Elevated temperature enhances neutrophil/macrophage function, T cell proliferation, and interferon activity while reducing pathogen replication.
Fever is therapeutic, not harmful (unless >40-41°C). Suppressing fever with antipyretics (NSAIDs) may prolong illness by impairing immune function. In cPNI, fever is supported unless dangerously high or in vulnerable populations. The magnitude of fever reflects immune competence—immunocompromised patients may lack fever response. Socioeconomic factors affect fever response: poor individuals often show higher fever (chronic inflammation), while wealthy may show blunted response (chronic stress, HPA dysregulation).
- Defined as core temperature >38°C (100.4°F)
- Triggered by pyrogenic cytokines: IL-1β, IL-6, TNF, IL-8
- Mediated by PGE2 acting on hypothalamic EP3 receptors
- Enhances immune function: neutrophil activity, T cell proliferation, interferon production
- Inhibits pathogen replication (most bacteria/viruses optimized for 37°C)
- Increases metabolic rate ~13% per 1°C elevation
- Adaptive response that improves survival in infection
- NSAIDs suppress fever by inhibiting COX-2 and PGE2 synthesis
- Febrile seizures (<5% of children) are usually benign
- Dangerous above 41°C (protein denaturation, enzyme dysfunction)
- IL-1β — Primary pyrogenic cytokine inducing fever
- IL-6 — Pyrogenic cytokine contributing to fever and acute phase response
- TNF — Pyrogenic cytokine; part of inflammatory cascade triggering fever
- PGE2 — Prostaglandin mediating fever signal to hypothalamus
- COX-2 — Enzyme producing PGE2 in response to pyrogenic cytokines
- hypothalamus — Thermoregulatory center; preoptic area sets temperature set-point
- circumventricular organs — Lack BBB; sense peripheral cytokines to signal hypothalamus
- inflammation — Fever is part of acute inflammatory response
- immune system — Fever enhances multiple immune functions
- T cells — Proliferation and function enhanced at elevated temperature
- macrophages — Phagocytic activity enhanced by fever
- NSAIDs — Inhibit COX-2, blocking fever; may prolong illness
- sickness behavior — Fever part of coordinated sickness behavior syndrome
- acute phase response — Fever triggers hepatic acute phase protein production
- metabolism — Fever increases basal metabolic rate
- infection — Fever is primary defense against bacterial and viral infections
- chronic stress — HPA dysregulation can blunt fever response
- socioeconomic status — Poor show higher fever (inflammation); wealthy show lower (stress)
- antipyretics — Suppress fever but may impair immune defense