Fever is defined as a measured body temperature of at least 38℃ (100.4℉). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. This process increases the physiologic “set-point” of body temperature. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever is a symptom of a wide array of diseases; therefore, an accurate history and review of other symptoms are crucial in finding the cause. The major etiologies of fever include infectious (most common), non-infectious, neurogenic, and drug-induced. High fever can have systemic effects that put the individual at risk of both short- and long-term dysfunction. In severe cases, fever may lead to death if untreated.

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  • Fever is defined as a measured temperature of at least 38°C (100.4°F).
  • Normal body temperature fluctuates in a diurnal variation. Normal fluctuation is between 1°C and 1.3°C (1.8°F and 2.4°F) daily with:
    • Lowest-noted temperature between 2 am and 8 am
    • Highest-noted temperature between 4 am and 9 pm
  • Temperature varies based on the body site used for measurement (e.g., rectal is higher than oral)
  • Normal temperature elevations occur after:
    • Vigorous exercise
    • Eating
    • Ovulation



  • Most common cause
  • Examples: influenza, common cold, pneumonia, malaria, HIV, infectious mononucleosis, gastroenteritis


  • Caused by direct damage to the hypothalamus from: 
    • Central nervous system (CNS) trauma
    • Intracerebral bleeding
    • Increase in intracranial pressure
  • Characterized by a high temperature and resistance to antipyretic therapy; not associated with sweating


  • Possible pathways: 
    • Interference with the physiological mechanisms of heat loss and central temperature regulation
    • Direct damage to tissues
    • Stimulation of an immune response
    • Pyrogenic properties of the drug
  • Common drug classes:
    • Anticonvulsants (carbamazepine, phenytoin, phenobarbital)
    • Antimicrobials (minocycline, beta-lactams, sulfonamides, nitrofurantoin)
    • Antidepressants (serotonin syndrome secondary to selective serotonin reuptake inhibitor (SSRI) intake)
    • Allopurinol
    • Heparin
    • Antihistamines
    • Illegal drugs: amphetamines, cocaine

Other conditions

  • Endocrinopathies (hyperthyroidism, pheochromocytoma)
  • Pulmonary emboli
  • Neoplasms
  • Tissue damage (myocardial infarction, burns, surgery, hemorrhage, crush syndrome)
  • Autoinflammation (arthritis, irritable bowel syndrome (IBS))

Related videos


  • Body temperature is regulated by the CNS at the level of the hypothalamus. 
  • Fever is a normal physiologic phenomenon caused by the release of either exogenous or endogenous pyrogens (any substance that causes fever). 
  • When a fever occurs, the hypothalamic thermoregulatory center shifts its set-point upward (similar to the thermostat in a home). 
  • This upward shift is due toprostaglandin E2 (PGE2)in the preoptic area of the hypothalamus (increased PGE2 is caused by circulating pyrogens).
  • Endogenous pyrogens:
    • Produced by inflammation, trauma, or antigen-antibody complexes
      • Interleukin-1 (IL-1)
      • IL-6
      • TNF-𝛼
      • Interferon-γ
    • Activates the arachidonic acid pathway, which releases PGE2 → activates the preoptic area of the hypothalamus → increases temperature set-point
  • Exogenous pyrogens:
    • Primarily from microbes:
      • Lipopolysaccharides (LPS) of gram-negative bacteria
      • Endotoxins
      • Exotoxins

Physiologic effects of fever

  • Heat conservation: vasoconstriction
    • Increases heat production in the periphery
    • Causes a subjective cold sensation in the hands and feet as blood is shunted from the periphery to internal organs
  • Heat production: thermogenesis of muscle and adipose tissue 
    • Increased core temperature by release of adenosine triphosphate (ATP) 
    • Muscle heat production → shivering
    • Adipose tissue heat production → in neonates due to a higher percentage of brown fat
  • Once the hypothalamic set-point is reset downward, heat loss occurs through:
    • Vasodilation, sweating, and behavior changes; may be due to a reduction in pyrogenic cytokines or the use of antipyretics
Time course of a typical fever

Time course of a typical fever

Image by Lecturio.
Pathway of fever

Mechanisms of fever generation

A stressor of the body (e.g., infection, injury, trauma) incites lymphocytes to release cytokines which, in turn, stimulate the hypothalamus.
Within the hypothalamus, the vascular organ of lamina terminalis, or supraoptic crest (OVLT) activates cyclooxygenases (COX), which catalyzes the formation of prostaglandins (PGE2).
These hormone-like substances produce fever by activating cold-sensitive (CS) neurons and inhibiting warm-sensitive (WS) neurons.

Image by Lecturio.

Clinical Presentation

Common symptoms

  • Rigors (shivering)
  • Sweats
  • Chills
  • Flushing of skin
  • Tachycardia or palpitations
  • Lethargy

Types of fever patterns

Types of fever patterns

Types of fever patterns

Image by Lecturio.

Effects of Fever

Beneficial effects

  • Endogenous pyrogens:
    • Influence the recruitment and function of many types of immune cells
      • Enhance phagocytosis by neutrophils and macrophages
      • Enhance antigen presentation by macrophages and T cells
    • Decrease the levels of trace metals available (iron and zinc)
      • Helps to inhibit microbial reproduction
  • High temperatures (39°C41°C):
    • Directly inhibit the growth of some bacteria
    • May also inhibit motility and capsule/cell wall formation
  • Increases antimicrobial activity of some antibiotics

Adverse effects

  • Direct cellular damage by cytokines and inflammation: causes both local and systemic effects (summarized below)
  • May provoke sepsis syndrome
  • Very high fevers (> 41°C): increase host metabolic demands → may result in congestive heart failure (CHF) and ischemia
Table: Adverse effects of cytokines
  • Membrane, mitochondrial, and DNA damage
  • Stimulation of excitotoxic mechanisms
  • Protein denaturation
  • Cell death
  • Cytokine stimulation
  • Inflammatory response
  • Vascular stasis
  • Extravasation
  • Edema
  • Endotoxemia
  • Gut bacterial translocation

Clinical Relevance

The following conditions are associated with elevated body temperature:

  • DRESS (drug rash with eosinophilia and systemic symptoms) syndrome: a delayed, severe hypersensitivity reaction to drugs. Often caused by allopurinol, anticonvulsants, and sulfonamides. Besides fever, symptoms include eosinophilia, diffuse rashes, lymphadenopathy, atypical lymphocytosis, thrombocytopenia, and hepatitis. Treated by withdrawal of the causative agent. The case fatality rate is 10%.
  • Malignant hyperthermia: a rare genetic condition characterized by the sudden appearance of life-threatening symptoms, such as fever > 40°C with muscle rigidity and hemodynamic instability, in response to certain drugs used for anaesthesia. Diagnosis is based on clinical presentation in an acute event or through genetic testing following the diagnosis in a relative. Treatment is with intravenous dantrolene.
  • Neuroleptic malignant syndrome (NMS): a life-threatening condition in response to antipsychotic and neuroleptic drugs. Presents with high fever, muscle rigidity, altered mental status, and dysautonomia. Treatment includes withdrawal of the drug and antidotes such as dantrolene and amantadine.
  • Serotonin syndrome: a condition in response to serotonergic drugs, e.g., antidepressants such as SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs). Presents with agitation, confusion, hyperthermia, autonomic hyperactivity, and rigidity. Treatment consists of discontinuation of the causative agent.

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