Fever: Definition, Pathogenesis & Classification

Definition

• Normal body temperature: 36–37.5°C (96.8–99.5°F)
• Fever is generally defined as a core temperature > 38°C (100.4°F)

Pathogenesis

1. Pyrogens

2. Mechanism (Step-by-step)

1. Bacteria/debris are phagocytized by macrophages, leukocytes, and killer lymphocytes
2. These cells release interleukin-1 (IL-1) — also called leukocyte pyrogen / endogenous pyrogen
3. IL-1 reaches the anterior hypothalamus and stimulates synthesis of prostaglandin E₂ (PGE₂)
4. PGE₂ raises the hypothalamic set-point temperature
5. The hypothalamus now perceives normal body temperature as "too low" → activates heat conservation (vasoconstriction, piloerection) and heat production (shivering)
6. Body temperature rises to match the new set-point → fever

As little as one ten-millionth of a gram of LPS endotoxin, acting via leukocytes, can cause fever through nanogram amounts of IL-1. — Guyton and Hall, p. 900

Why Aspirin Reduces Fever

Body Temperature Ranges

Figure: Body temperatures under different conditions — Guyton & Hall, p. 900

Classification of Fever

A. By Temperature Grade

B. By Duration

C. By Fever Pattern (Pyrexia Patterns)

D. By Etiology

E. By Pathophysiology (Mediator Type)

Fever vs. Hyperthermia

Hypothalamic Thermostat & Classification of Fever

Part 1 — The Hypothalamic Thermostat

What is the Thermostat?

"This shift of the set point from 'normothermic' to febrile levels very much resembles the resetting of the home thermostat to a higher level in order to raise the ambient temperature in a room." — Harrison's Principles of Internal Medicine 22E, p. 178

Normal Set-Point: ~37°C (98.6°F)

• Heat production (metabolism, shivering, non-shivering thermogenesis in liver)
• Heat loss (vasodilation, sweating, radiation, respiration)

How the Thermostat is Reset in Fever

Pyrogens (Harrison's Classification)

• Lipopolysaccharide (LPS/endotoxin) of gram-negative bacteria — most potent (2–3 ng/kg causes fever in humans)
• Cell-wall components of gram-positive bacteria
• Superantigens: S. aureus TSST-1, staphylococcal enterotoxins, streptococcal pyrogenic exotoxins (fever at 1–10 μg/kg)

• IL-1 (fever at 10–100 ng/kg)
• IL-6 (fever at 1–10 μg/kg — requires higher dose)
• TNF-α (fever at 10–100 ng/kg)
• Ciliary neurotropic factor (IL-6 family)
• IFN-α (fever as side effect of therapy)

Antipyretic Mechanism

Part 2 — Fever vs. Hyperthermia (Harrison's)

"Hyperthermia is characterized by an uncontrolled increase in body temperature that exceeds the body's ability to lose heat. The setting of the hypothalamic thermoregulatory center is unchanged." — Harrison's 22E, p. 178

Part 3 — Classification of Fever

A. Harrison's Classification (by Etiology / Disease Category)

B. Harrison's — Fever Patterns (by Periodicity)

C. Davidson's Classification of Fever

• Acute — < 2 weeks
• Chronic — > 2 weeks (raises suspicion for TB, endocarditis, malignancy, connective tissue disease)
• Pyrexia of Unknown Origin (PUO) — fever > 38.3°C on multiple occasions, > 3 weeks duration, no diagnosis after 1 week of investigation

Key Takeaways

1. The hypothalamic thermostat works exactly like a room thermostat — fever is simply its set point being deliberately raised by PGE₂
2. Harrison's classifies fever by etiology (infection, malignancy, autoimmune, drug, endocrine, hypothalamic) and periodicity (tertian, quartan, Pel-Ebstein, relapsing)
3. Davidson's emphasises fever patterns (continuous, remittent, intermittent, hectic, undulant, inverse) as clinical diagnostic tools
4. Fever responds to antipyretics; true hyperthermia does not — a critical bedside distinction

Sepsis vs. Septic Shock

Historical Context & Evolution of Definitions

• Sepsis-1 (1992): Sepsis = suspected infection + ≥2 SIRS criteria; Septic shock = sepsis-induced hypotension (SBP < 90 mmHg) despite adequate fluids
• Sepsis-2 (2003): Expanded clinical/laboratory criteria
• Sepsis-3 (2016): Current standard — abandoned SIRS criteria entirely, replaced by organ dysfunction scoring

"Sir William Osler opined: 'except on few occasions, the patient appears to die from the body's response to infection rather than from it.'" — Harrison's Principles of Internal Medicine 22E, p. 2360

Current Definitions (Sepsis-3, 2016)

Sepsis

Life-threatening organ dysfunction caused by a dysregulated host response to infection Operationally defined as: acute increase in SOFA score ≥ 2 points due to infection — Barash Clinical Anesthesia 9E; Goldman-Cecil Medicine

Septic Shock

A subset of sepsis with underlying circulatory, cellular, and metabolic abnormalities so severe that the risk of death is substantially higher than sepsis alone Operationally defined as:

• Vasopressor requirement to maintain MAP ≥ 65 mmHg PLUS
• Serum lactate > 2 mmol/L (>18 mg/dL) despite adequate volume resuscitation — Goldman-Cecil Medicine, p. 1090; Barash Clinical Anesthesia 9E, p. 4829

Key Differences at a Glance

SOFA Score (Sequential Organ Failure Assessment)

1. Respiratory rate ≥ 22/min
2. Altered mental status (GCS < 15)
3. Systolic BP ≤ 100 mmHg

Pathophysiology

Common to Both — Dysregulated Host Immune Response

1. PAMPs (Pathogen-Associated Molecular Patterns — e.g., LPS from gram-negative bacteria, cell-wall components of gram-positives) and DAMPs (Damage-Associated Molecular Patterns — histones, HMGB1, ATP) are released
2. Recognised by Pattern Recognition Receptors (PRRs): Toll-like receptors (TLRs), NOD receptors, RAGE, RIG-I
3. Triggers massive release of pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and chemokines
4. Neutrophils activate → form NETs (Neutrophil Extracellular Traps) → microvascular thromboses
5. Endothelial dysfunction → capillary leak → oedema, hypotension

What Distinguishes Septic Shock

"Even in the case of normal or seemingly adequate CO and oxygen delivery, metabolic needs are increased during sepsis, and the ability of the tissues to extract and utilise oxygen may be impaired. Thus, metabolic acidosis may be present despite normal levels of oxygen transport." — Barash Clinical Anesthesia 9E, p. 4829

Organ Complications (Harrison's, p. 2365)

Management Principles (Surviving Sepsis Campaign)

Summary Spectrum

Infection
    ↓
Sepsis  (infection + SOFA ↑≥2)
    ↓
Septic Shock  (sepsis + vasopressor needed + lactate >2 mmol/L)
    ↓
Multi-Organ Dysfunction Syndrome (MODS)  →  Death