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Chapter 18: Fever

Authors: Neeraj K. Surana; Charles A. Dinarello; Reuven Porat

Introduction

  • Body temperature is controlled by the hypothalamus.
  • Neurons in the preoptic anterior hypothalamus and posterior hypothalamus receive signals from:
    • Peripheral nerves transmitting information from warmth/cold receptors in the skin.
    • The temperature of the blood bathing the region.
  • The thermoregulatory center integrates these signals to maintain normal temperature.
  • In a neutral environment, the human metabolic rate produces more heat than needed to maintain a core body temperature of 36.5–37.5°C (97.7–99.5°F).
  • Normal body temperature is maintained despite environmental variations due to:
  • Balancing excess heat production from metabolic activity in muscle and liver.
  • Heat dissipation from the skin and lungs.
  • Study findings:
  • Mean oral temperature: 36.6°C.
  • A temperature of >37.7°C (>99.9°F) defines a fever.
  • Higher ambient temperatures correlate with higher baseline body temperatures.
  • Body temperatures show diurnal and seasonal variation:
    • Lower in the morning (8 A.M.) and during summer.
    • Higher in the afternoon (4 P.M.) and during winter.
  • Baseline temperatures are affected by:
    • Age: Decrease by 0.02°C per 10-year increase.
    • Demographics: African-American women have temperatures 0.052°C higher than white men.
    • Comorbid conditions: Cancer (+0.02°C), hypothyroidism (–0.01°C).
  • An increase in baseline temperature by 0.15°C leads to a 0.52% absolute increase in 1-year mortality.
  • Temperature measurement differences:
  • Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings.
  • Lower oral readings may be due to mouth breathing.
  • Tympanic membrane thermometers can be variable.
  • Menstruating women:
  • A.M. temperature is lower during the 2 weeks before ovulation.
  • Rises by ~0.6°C (1°F) with ovulation until menses.
  • Circadian rhythm amplitude remains the same during the luteal phase.

Fever Versus Hyperthermia

  • Fever:
  • An elevation of body temperature exceeding normal daily variation.
  • Occurs with an increase in the hypothalamic set point (e.g., from 37°C to 39°C).
  • Mechanisms involved:
    • Activation of neurons in the vasomotor center.
    • Vasoconstriction begins, especially in hands and feet.
    • Shunting of blood away from periphery to internal organs.
    • Shivering may commence to increase heat production.
    • Behavioral adjustments (e.g., adding clothing) help raise body temperature.
  • The body maintains the new febrile temperature until the set point is reset downward.
  • Hyperpyrexia:
    • Fever of >41.5°C (>106.7°F).
    • Can occur in severe infections or CNS hemorrhages.
  • Hyperthermia:
  • An uncontrolled increase in body temperature exceeding the body's ability to lose heat.
  • Hypothalamic set point is unchanged.
  • Does not involve pyrogenic molecules.
  • Caused by exogenous heat exposure or endogenous heat production.
  • Examples include heat stroke and drug-induced impairment of thermoregulation.
  • Important distinctions from fever:
    • Skin may be hot and dry.
    • Does not respond to antipyretics.

Pathogenesis of Fever

Pyrogens

  • Pyrogen: Any substance that causes fever.
  • Exogenous pyrogens:
  • Derived from outside the patient.
  • Include microbial products, toxins, or whole microorganisms.
  • Examples:
    • Lipopolysaccharide (endotoxin) from gram-negative bacteria.
    • Enterotoxins from Staphylococcus aureus and group A/B streptococci (superantigens).
    • Toxins associated with toxic shock syndrome.

Pyrogenic Cytokines

  • Small proteins regulating immune and inflammatory processes.
  • Pyrogenic cytokines (formerly endogenous pyrogens):
  • Interleukin (IL)-1
  • IL-6
  • Tumor necrosis factor (TNF)
  • Ciliary neurotropic factor
  • Characteristics:
  • Cause fever when injected into humans at low doses.
  • Induced by a wide spectrum of bacterial and fungal products.
  • Also produced in non-infectious inflammatory processes.

Elevation of the Hypothalamic Set Point by Cytokines

  • During fever, levels of prostaglandin E2 (PGE2) are elevated in the hypothalamus.
  • Key events:
  • Pyrogenic cytokines enter systemic circulation.
  • Induce PGE2 synthesis in the brain and periphery.
  • PGE2 interacts with the EP-3 receptor essential for fever.
  • Leads to the release of cyclic AMP (cAMP), triggering the hypothalamic neurons to raise the set point.
  • Toll-like receptors on hypothalamic endothelium can also induce fever through PGE2 production.

Production of Cytokines in the CNS

  • Cytokines produced in the brain can cause hyperpyrexia.
  • Examples:
  • CNS hemorrhage, trauma, or infection can induce local cytokine production.
  • Cytokines act directly on the hypothalamus to raise the set point.

Approach to the Patient with Fever

History and Physical Examination

  • Determine exposure history, including contact with symptomatic individuals or vectors.
  • Consistent temperature measurement site is important.
  • Be aware that certain populations may have a blunted febrile response:
  • Newborns
  • Elderly patients
  • Patients with chronic hepatic or renal failure
  • Patients on glucocorticoids or anticytokine therapies

Laboratory Tests

  • Complete blood count with differential.
  • Look for juvenile or band forms, toxic granulations, and Döhle bodies.
  • Neutropenia may indicate viral infections.
  • Measure inflammatory markers:
  • C-reactive protein (CRP)
  • Erythrocyte sedimentation rate (ESR)
  • Circulating cytokine levels are generally not helpful.

Fever in Patients Receiving Anticytokine Therapy

  • Patients on anticytokine regimens are at increased risk of infections.
  • Blunted febrile response may occur.
  • Low-grade fever in these patients warrants thorough evaluation.
  • Similar concerns apply to patients on chronic glucocorticoids or NSAIDs.

Treatment of Fever

Decision to Treat Fever

  • Fever is a normal response, not an illness itself.
  • Antipyretic treatment does not harm and does not delay infection resolution.
  • Considerations for withholding antipyretics:
  • Evaluating effectiveness of antibiotics in bacterial infections.
  • Diagnosing unusual febrile diseases.
  • Monitoring characteristic fever patterns in certain diseases.

Anticytokine Therapy to Reduce Fever

  • Used in autoimmune and autoinflammatory diseases.
  • IL-1β is a common mediator of fever in these conditions.
  • Anakinra and canakinumab are examples of anticytokine therapies.

Mechanisms of Antipyretic Agents

  • Reduce elevated hypothalamic set point by decreasing PGE2 levels.
  • Cyclooxygenase inhibitors (e.g., NSAIDs) are potent antipyretics.
  • Acetaminophen inhibits cyclooxygenase activity in the brain.
  • Glucocorticoids inhibit phospholipase A2 and block pyrogenic cytokine mRNA transcription.

Regimens for the Treatment of Fever

  • Preferred antipyretic: Acetaminophen.
  • NSAIDs like ibuprofen can be used; avoid aspirin in children (risk of Reye’s syndrome).
  • Cooling methods (e.g., cooling blankets) may be used in hyperpyrexia but should be combined with antipyretics.
  • Treat fever aggressively in:
  • Patients with cardiovascular or pulmonary impairment.
  • Children with a history of seizures.

Note: This guide is structured to facilitate quick revision, highlighting key points and terminology related to fever as discussed in the provided context.