Seminar: Pathophysiology of Fever

1. Fever vs. Hyperthermia - How to Differentiate

Key teaching point: In hyperthermia, the thermoregulatory system is overwhelmed or bypassed - the hypothalamus WANTS to cool down but cannot. In fever, the hypothalamus deliberately raises the set point.

• Rosen's Emergency Medicine, Concepts and Clinical Practice, p. 123

2. Pyrogens - Types and Examples

A. Exogenous Pyrogens

1. Gene expression and synthesis of pyrogenic cytokines (endogenous pyrogens)
2. Direct induction of cyclooxygenase-2 (COX-2) via TLR-4 signaling → PGE2 production

B. Endogenous Pyrogens

"Substances that induce fever are called pyrogens and include bacterial products (exogenous pyrogens, e.g., LPS) and cytokines, principally IL-1 and TNF (called endogenous pyrogens)."

• Robbins, Cotran & Kumar - Pathologic Basis of Disease

3. Why Are Chills Seen in Fever?

1. Pyrogenic cytokines (IL-1, TNF-α, IL-6) reach the hypothalamus.
2. PGE2 is synthesized → the hypothalamic thermostat set point is raised (e.g., from 37°C to 39°C).
3. At this point, the actual body temperature is still 37°C - the body perceives itself as too cold relative to the new set point.
4. The hypothalamus activates heat-conserving and heat-generating mechanisms to bring the actual temperature up to the new set point:
   • Peripheral vasoconstriction → reduced heat loss through the skin → patient feels cold, skin becomes pale/mottled
   • Piloerection ("goosebumps") → conserves heat (vestigial mechanism)
   • Shivering (rigors) → involuntary rhythmic skeletal muscle contractions → generates heat through increased metabolic rate
   • Behavioral changes → patient seeks warmth, curls up, wraps in blankets
   • ↑ Brown fat catabolism → non-shivering thermogenesis
5. Once the actual body temperature reaches the new set point, chills stop and the patient feels hot.

"PGE2 raises the set point of the temperature range by a combination of effects, including peripheral vasoconstriction, increased metabolic heat production, shivering, and behavioral changes that conserve heat."

• Rosen's Emergency Medicine, p. 123

4. Defervescence and Its Mechanism

Two Patterns of Defervescence:

Mechanism of Action of Defervescence:

1. Pyrogenic cytokines decrease → PGE2 levels fall in the hypothalamus.
2. The set point returns to normal (37°C).
3. Now the actual body temperature (still elevated at, say, 39°C) is above the new normal set point.
4. The hypothalamus activates heat-dissipating mechanisms:
   • Cutaneous vasodilation → increased heat loss through the skin → patient appears flushed/red
   • Profuse sweating → evaporative heat loss
   • Behavioral changes → removes blankets, seeks cool environment
5. Body temperature gradually falls back to normal.

5. How NSAIDs Reduce Fever

Step-by-step mechanism:

1. Exogenous pyrogens (e.g., LPS) or inflammatory stimuli activate immune cells → release of IL-1β, TNF-α, IL-6
2. These endogenous pyrogens act on the hypothalamic vasculature → upregulate Cyclooxygenase-2 (COX-2)
3. COX-2 converts arachidonic acid to PGE2 (Prostaglandin E2)
4. PGE2 binds to EP1 and EP3 receptors in the preoptic area of the hypothalamus → raises temperature set point
5. NSAIDs (e.g., ibuprofen, aspirin, naproxen) → competitively and irreversibly (aspirin) or reversibly (other NSAIDs) inhibit COX-1 and COX-2
6. ↓ PGE2 synthesis → set point falls back to normal → defervescence occurs

"NSAIDs, including aspirin, reduce fever by inhibiting prostaglandin synthesis."

• Robbins, Cotran & Kumar - Pathologic Basis of Disease

"Medications such as nonsteroidal anti-inflammatory drugs and aspirin block the activity of enzymes involved in the synthesis of prostaglandin E2."

• Goldman-Cecil Medicine

6. Metabolic Effects of Fever

7. How Fever is Beneficial and Harmful

Beneficial Effects of Fever

"An elevated body temperature has been shown to help amphibians ward off microbial infections, and it is possible that fever is a protective host response in mammals as well."

• Robbins, Cotran & Kumar

"When patients fail to develop a fever despite severe bacterial infection, morbidity and mortality tend to be higher."

• Goldman-Cecil Medicine

Harmful Effects of Fever

8. Febrile Seizures

Definition

Classification

Why Does Fever Cause Seizures?

• Rapid rise in temperature (not necessarily very high temperature) is the key trigger
• Fever increases neuronal excitability: depolarizes neuronal membranes, alters ion channel kinetics, increases synaptic transmission
• The developing brain (myelination incomplete) has a lower seizure threshold compared to adults
• Genetic predisposition plays a role (polygenic inheritance; some families show autosomal dominant transmission with mutations in SCN1A sodium channels)

Recurrence Risk

• 30-40% of children will have at least one recurrence
• Predictors of recurrence: age <1 year at first seizure, family history of febrile seizures/epilepsy, daycare attendance (↑ febrile illnesses)

Risk of Later Epilepsy

• Risk of afebrile epilepsy by age 25: ~7% (vs. ~1% in general population)
• Risk increases with complex features:
  • 1 complex feature: 6-8%
  • 2 complex features: 17-22%
  • All 3 complex features: ~49%
• Febrile status epilepticus can injure the hippocampus → hippocampal sclerosis → temporal lobe epilepsy

Genetic Associations

• Dravet syndrome (SMEI) - truncating mutation in SCN1A; presents with febrile seizures in infancy, progresses to afebrile seizures and cognitive decline
• Other genetic epilepsy syndromes can begin with febrile seizures

Management

• Acute: Diazepam (rectally or IV) to terminate prolonged seizures
• Prophylaxis: Chronic anti-seizure drugs are generally NOT recommended (side effects outweigh benefit for simple febrile seizures)
• For high-risk children: Rectal diazepam at time of fever to prevent recurrence (avoids chronic drug exposure)
• Chronic phenobarbital prophylaxis: Shown to have substantial cognitive side effects (Farwell et al., 1990) - not recommended

Summary Table: The Fever Cascade

Infection/Inflammation/Neoplasm
        ↓
Immune cells (macrophages, monocytes)
        ↓
Exogenous pyrogens → Endogenous pyrogens (IL-1β, TNF-α, IL-6, IFN-γ)
        ↓
Preoptic anterior hypothalamus
        ↓
↑ COX-2 → ↑ PGE2 (EP1/EP3 receptors)
        ↓
RAISED THERMOSTAT SET POINT
        ↓
Heat conservation: vasoconstriction + shivering (CHILLS)
        ↓
Core temp reaches new set point → FEVER maintained
        ↓
Cause resolves / NSAIDs → ↓ PGE2 → set point normalizes
        ↓
Heat dissipation: vasodilation + sweating (DEFERVESCENCE)

• Rosen's Emergency Medicine - Concepts and Clinical Practice (Pathophysiology of Fever, p. 123)
• Robbins, Cotran & Kumar - Pathologic Basis of Disease (Systemic Effects of Inflammation)
• Goldman-Cecil Medicine, International Edition (Pathobiology of Fever)
• Janeway's Immunobiology, 10e (Acute-Phase Response)
• Goodman & Gilman's Pharmacological Basis of Therapeutics (Febrile Convulsions)
• Bradley and Daroff's Neurology in Clinical Practice (Febrile Seizures)

Viva Questions: Pathophysiology of Fever

BASIC / OPENING QUESTIONS

MECHANISM-BASED QUESTIONS

• Aspirin (acetylsalicylic acid): Causes irreversible acetylation of the serine residue in the active site of both COX-1 and COX-2. New enzyme must be synthesized to restore function. In platelets (which lack nuclei), COX-1 inhibition is permanent for the platelet's lifetime (~10 days).
• Ibuprofen: Causes reversible, competitive inhibition of both COX isoforms. Effect wears off as the drug is cleared.
• Both reduce fever by the same endpoint: ↓ PGE2 → set point normalizes.

TRICKY / APPLIED QUESTIONS

1. No ceiling mechanism: In fever, the body's own anti-pyretic mechanisms (endogenous antipyretics like arginine vasopressin, α-MSH, IL-10) and the fixed dose of pyrogen limit how high the temperature rises - usually not beyond 41°C in true fever. In hyperthermia, there is no such regulatory ceiling; temperatures can exceed 42-43°C.
2. No adaptive response: Fever is a coordinated response where the body "wants" the higher temperature. In hyperthermia, the hypothalamus is desperately trying to cool down but cannot. Temperatures above 41-42°C cause direct protein denaturation, enzyme dysfunction, and multi-organ failure.

• Arginine vasopressin (AVP) - released from hypothalamus; acts centrally to limit fever
• α-Melanocyte-stimulating hormone (α-MSH) - potent antipyretic and anti-inflammatory peptide
• IL-10 - anti-inflammatory cytokine; inhibits macrophage activation and cytokine production
• Glucocorticoids - cortisol suppresses cytokine production and PGE2 synthesis These constitute a negative feedback system - as fever rises, anti-inflammatory signals also rise to keep the response proportionate.

• The upper limit of fever is controlled by endogenous antipyretics (AVP, α-MSH, IL-10) - these kick in as temperature rises, preventing runaway fever.
• Febrile seizures depend not so much on the absolute temperature but on the rate of temperature rise - a rapid rise from 37°C to 38.5°C can trigger a seizure just as readily as a higher temperature. The immature, incompletely myelinated brain of young children has a lower seizure threshold and is more sensitive to rapid temperature changes and their effects on ion channel kinetics.

• 1 complex feature (prolonged >15 min, focal, or >1 in 24h): 6-8%
• 2 complex features: 17-22%
• All 3 complex features: ~49%

• Pre-existing neurodevelopmental abnormalities
• Family history of epilepsy
• Febrile status epilepticus (can cause hippocampal injury → sclerosis → temporal lobe epilepsy)
• Recurrent febrile seizures

• TNF-α and IL-1 drive accelerated release of granulocytes from the bone marrow (explaining the early neutrophilia with left shift)
• IL-6 is integral to the production of acute-phase reactants (CRP, fibrinogen, haptoglobin, serum amyloid A)
• Prolonged infection → colony-stimulating factors (CSFs) from macrophages → proliferation of precursors in bone marrow

• Typhoid fever (Salmonella typhi)
• Leptospirosis
• Rickettsiosis
• Dengue fever
• Legionellosis
• Babesiosis

CLASSIC TRAP / EXAMINER FAVOURITE

• Overwhelming infection with immune exhaustion
• Elderly or immunocompromised patient (blunted cytokine response)
• Antipyretic medication masking fever
• Associated with development of septic shock and worse outcomes