Fever

Definition

Fever (pyrexia) is a regulated rise in core body temperature above the normal range, caused by an upward shift in the hypothalamic "set point" - not a failure of thermoregulation. This distinguishes it from hyperthermia, where temperature rises because heat-dissipating mechanisms are overwhelmed or fail (e.g., heat stroke, malignant hyperthermia) while the hypothalamic set point stays normal (Costanzo Physiology, 7th ed.).

Normal body temperature varies with time of day, measurement site, and individual, but fever is generally accepted as an oral temperature above 38.0°C (100.4°F).

Pathophysiology

Pyrogens trigger fever. These are either:
- Exogenous pyrogens - bacteria, viruses, fungi, and their toxins (classically lipopolysaccharide/endotoxin from gram-negative bacteria)
- Endogenous pyrogens - cytokines released by the host's own phagocytes
Cytokine cascade: Phagocytic cells (macrophages, monocytes, tissue macrophages) engulf the pyrogenic stimulus and release cytokines - chiefly interleukin-1 (IL-1), along with IL-6 and tumor necrosis factor (TNF). IL-1 (also called "leukocyte pyrogen" or endogenous pyrogen) reaches the hypothalamus and can raise body temperature within 8-10 minutes (Guyton and Hall Textbook of Medical Physiology, p. 900).
Set-point resetting: These cytokines act on the anterior hypothalamus (preoptic area) to increase local prostaglandin E2 synthesis. Prostaglandin E2 is what actually raises the hypothalamic set point (Costanzo Physiology, 7th ed.).
Effector response: Once the set point rises, the current (normal) core temperature is "sensed" as too low, so the body activates heat-generating and heat-conserving mechanisms:
- Vasoconstriction (shunting blood away from the skin, reducing heat loss)
- Shivering and increased muscle/fat thermogenesis
- Piloerection and behavioral heat-seeking (curling up, adding blankets)
Temperature rises over a few hours to match the new set point (Guyton and Hall, Fig. 74.11).
Resolution: When the pyrogenic stimulus subsides or antipyretics are given, the set point falls back to normal. The hypothalamus then senses the current temperature as too high, triggering vasodilation and sweating (crisis/defervescence) to dissipate heat.

How antipyretics work

Aspirin, NSAIDs, and other cyclooxygenase (COX) inhibitors block prostaglandin E2 synthesis in the hypothalamus, interrupting the pathway pyrogens use to raise the set point - this is why they reduce fever but do not affect normal body temperature (Costanzo Physiology, 7th ed.). Corticosteroids reduce fever further upstream by suppressing production of the pyrogenic cytokines themselves.

Common causes

Infectious (most common overall): respiratory tract infections, gastrointestinal infections, urinary tract infections, skin/soft tissue infections - most acute respiratory and GI infections are viral
Non-infectious: autoimmune/inflammatory disease (e.g., adult-onset Still's disease, vasculitis), malignancy (especially lymphoma), drug fever, transfusion reactions, tissue infarction/necrosis, thromboembolism
Postoperative fever - classic mnemonic "five Ws": Wind (atelectasis/pneumonia), Water (UTI), Wound (surgical site infection), Walking (DVT/PE), Wonder drugs (drug fever, pseudomembranous colitis) (Tintinalli's Emergency Medicine; Goldman-Cecil Medicine)
Fever patterns can hint at etiology: continuous fever (typhoid/enteric fever), intermittent fever, remittent fever, and relapsing fever (e.g., Borrelia infections) (Park's Textbook of Preventive and Social Medicine; Medical Microbiology 9e)

Clinical evaluation

Workup depends on associated features:

History: onset, pattern, localizing symptoms, travel, exposures, medications, immune status
Examination for a focal source (respiratory, urinary, skin, wound, CNS)
Basic labs (CBC, blood cultures, urinalysis/urine culture) when no obvious source, plus imaging or site-specific cultures as indicated
Fever of unknown origin (FUO) is defined when fever persists despite a reasonable initial workup, and the differential expands to infection, malignancy, autoimmune disease, and drug fever.

Management principles

Treat the underlying cause (antimicrobials, discontinuation of offending drug, treatment of inflammatory disease, etc.)
Antipyretics (acetaminophen, NSAIDs) for comfort - fever itself is usually adaptive (it enhances neutrophil bactericidal activity and inhibits growth of some pathogens) and treating it does not clearly improve outcomes in most infections
Supportive care: hydration, nutrition
Exception: in some critical illness contexts (e.g., acute brain injury), fever may worsen outcomes and more aggressive temperature control is sometimes used - this remains an active area of study.

Recent evidence check

A 2024 systematic review/meta-analysis (PMID: 39538310) examined fever's impact on outcomes in non-anoxic acute brain injury, and a 2023 meta-analysis (PMID: 35366212) explored fever's "ambiguous role" in worsening outcome after intracerebral hemorrhage - both suggest that in specific neurocritical care populations, fever may be harmful rather than purely adaptive, which nuances the general teaching that fever should not be aggressively treated. This doesn't contradict standard fever management in general infections but is worth flagging for neuro-ICU contexts.

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