Why do some patients have a naturally low fever set point regulated by the hypothalamus?

Why Some Patients Never Get a Fever: Understanding Variations in Fever Response

Some patients may never develop fever during infection due to individual variations in hypothalamic temperature regulation, immune response differences, or underlying medical conditions that affect the fever response pathway. 1

Normal Temperature Regulation and Definition of Fever

• The anterior hypothalamus functions as the body's thermostat, regulating temperature by balancing heat production and loss through the sympathetic nervous system 2
• Normal body temperature varies by factors including age, gender, diurnal variation, and measurement site 1
• Evidence indicates that normal body temperature has been decreasing in the human population by 0.03°C per birth decade over the last 157 years 1
• Fever is clinically defined as a single temperature measurement ≥38.3°C according to Society of Critical Care Medicine and Infectious Diseases Society of America guidelines 1

Pathophysiology of Fever Response

• Fever occurs when the hypothalamic thermoregulatory set point is shifted upward, typically in response to infection or inflammation 2, 3
• The fever response is initiated by:
  • Exogenous pyrogens (microbial products) binding to Toll-like receptors (TLRs) 4
  • Production of endogenous pyrogens (pyrogenic cytokines) like IL-1, TNF-α, and IL-6 4
  • Prostaglandin E2 (PGE2) synthesis, which acts as the final mediator of fever by binding to EP3 receptors in the preoptic hypothalamus 3

Reasons Why Some Patients May Not Develop Fever

1. Hypothalamic Dysfunction

• Damage to the hypothalamus can impair temperature regulation, preventing normal fever response 5
• Neurogenic fever due to hypothalamic injury can cause temperature dysregulation, as demonstrated in stroke patients with hypothalamic damage 5
• Some individuals may have congenital or acquired variations in hypothalamic function that affect their ability to mount a fever response 5

2. Immune System Variations

• Individual differences in cytokine production or responsiveness can affect fever development 4
• Variations in prostaglandin synthesis or EP3 receptor function may result in altered fever responses 3
• Some patients may have genetic polymorphisms affecting the fever pathway components 4

3. Patient-Specific Factors That Can Suppress Fever

• Advanced age: Elderly patients often have blunted fever responses 1
• Immunosuppression: Patients with compromised immune systems may not mount typical fever responses 1
• Certain medications: Anti-inflammatory drugs, corticosteroids, and antipyretics can mask fever 1
• Specific conditions: End-stage liver disease, chronic renal failure, and congestive heart failure can affect fever response 1
• External cooling: Patients receiving continuous renal replacement therapy, extracorporeal membrane oxygenation, or those with large burns or open abdominal wounds may have altered temperature regulation 1

Clinical Implications

• The absence of fever in infected patients is associated with worse outcomes 1
• Patients who are hypothermic or euthermic may still have life-threatening infections 1
• Other signs of infection should be monitored in patients who don't develop fever, including:
  • Unexplained hypotension, tachycardia, tachypnea, confusion 1
  • Laboratory markers like leukocytosis, leukopenia, immature neutrophils, or thrombocytopenia 1
  • Elevated inflammatory markers like procalcitonin (PCT) or C-reactive protein (CRP) 1

Evolutionary Perspective

• Fever has evolved as a host defense mechanism preserved throughout the animal kingdom through hundreds of millions of years of evolution 6
• The association between increased body temperature and decreased mortality/morbidity during infection suggests fever is beneficial 6
• Individual variations in fever response may represent evolutionary adaptations to different environmental or pathogenic challenges 6

Practical Considerations

• When evaluating patients with suspected infection who don't develop fever, consider alternative diagnostic approaches 1
• In critically ill patients without fever but with suspected infection, recommendations for evaluation still apply 1
• For accurate temperature assessment, central temperature monitoring methods (pulmonary artery catheters, bladder catheters, esophageal thermistors) are most reliable 1
• When central monitoring is unavailable, oral or rectal temperatures are preferred over less reliable methods like axillary or tympanic measurements 1