What is the physiology behind infection-induced fever and its treatment?

The Physiology of Infection-Induced Fever

Fever is a physiologic mechanism that has beneficial effects in fighting infection rather than being a primary illness itself. 1, 2

Mechanism of Fever Generation

• Fever results from the body's natural response to exogenous or endogenous pyrogens that trigger a cascade of inflammatory responses 3
• When pathogens invade the body, they release components (exogenous pyrogens) such as lipopolysaccharides from gram-negative bacteria that are recognized by immune cells 4
• These immune cells (primarily macrophages) then produce endogenous pyrogens, including cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) 1
• These cytokines act on the hypothalamus, specifically the preoptic area, causing the release of prostaglandin E2 (PGE2) 5
• PGE2 raises the hypothalamic set point for body temperature, triggering physiological responses to increase core temperature 5
• The body then initiates heat-conserving and heat-generating mechanisms including:
  • Peripheral vasoconstriction to reduce heat loss
  • Increased metabolic rate
  • Shivering to generate heat 2

Benefits of Fever in Infection

• Fever enhances immune function by:
  • Increasing neutrophil production and activity
  • Enhancing T-lymphocyte proliferation
  • Facilitating interferon production
  • Inhibiting replication of some pathogens that are temperature-sensitive 2, 5
• Studies suggest that failure to mount a febrile response is associated with poor outcomes in certain infections 5
• Retrospective studies in humans and animal models indicate that fever or analogous thermal upregulation has positive effects on defense against infection 5

Diagnostic Significance of Fever

• Fever is a common early indicator of infection, occurring in 26-88% of adult ICU patients 1
• However, fever is not always present in infections and can be absent, especially in older and immunocompromised patients 3
• Laboratory tests including complete blood count, C-reactive protein, erythrocyte sedimentation rate, and procalcitonin do not have sufficient sensitivity and specificity to definitively detect or rule out an infectious cause of fever 3
• Serum procalcitonin levels can be employed as an adjunctive diagnostic tool for discriminating infection as the cause for fever, with levels rising within 2-3 hours of onset 4
• Procalcitonin levels correlate with severity: systemic inflammatory response syndrome (0.6-2.0 ng/mL), severe sepsis (2-10 ng/mL), and septic shock (10 ng/mL) 4

Treatment Considerations

• The primary goal of treating fever should be to improve overall comfort rather than focus on normalization of body temperature 2
• Antipyretic therapy should not be instituted routinely for every febrile episode but should be based on evaluation of relative risks in the individual case 5
• Antipyretic drugs are effective in diminishing fever but may suppress signs of ongoing infection 5
• Fever may have deleterious effects in the context of borderline cardiovascular or neurologic function or pregnancy 5
• When treating infection-induced fever, addressing the underlying cause through appropriate antimicrobial therapy is essential 1, 6

Non-Infectious Causes of Fever to Consider

• Drug-induced fever can occur days after administration and may take 1-3 days to resolve after removing the offending agent 4
• Malignant hyperthermia and neuroleptic malignant syndrome are important syndromes to consider when fever is especially high 4
• Withdrawal of certain drugs (alcohol, opiates, barbiturates, and benzodiazepines) may be associated with fever, often with tachycardia, diaphoresis, and hyperreflexia 4

Understanding the physiological mechanisms of fever helps clinicians appreciate its role as a natural defense mechanism while appropriately managing potential complications in vulnerable populations.