🌡️ FEVER - Complete Topic

1. DEFINITION OF NORMAL BODY TEMPERATURE

• Mean oral temperature: 36.6°C (95% CI: 35.7-37.3°C) based on a study of 35,000 individuals
• Fever is defined as body temperature >37.7°C (>99.9°F), representing the 99th percentile for healthy individuals
• Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings
• Tympanic (unadjusted mode) values are ~0.8°C lower than rectal temperatures

• Diurnal: Low at 8 AM, high at 4 PM
• Seasonal: Lower in summer, higher in winter
• Age: Decreases by 0.02°C per 10 years
• Menstrual cycle: Temperature rises ~0.6°C with ovulation and remains elevated until menses

2. FEVER vs. HYPERTHERMIA

Key point: "Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point (e.g., from 37°C to 39°C)." - Harrison's 22e, p.177

3. PATHOGENESIS OF FEVER

Step-by-step mechanism:

1. Exogenous pyrogens (bacteria, viruses, toxins, immune complexes) are recognized by monocytes, macrophages, dendritic cells, and endothelial cells
2. These cells produce endogenous pyrogens (cytokines):
   • IL-1α and IL-1β (most potent)
   • TNF (Tumor Necrosis Factor)
   • IL-6
   • IFN-α, IFN-β, IFN-γ
   • Ciliary neurotrophic factor (CNTF)
3. These cytokines act on the organum vasculosum of the lamina terminalis (OVLT) - a circumventricular organ lacking a blood-brain barrier, adjacent to the anterior hypothalamus
4. At the OVLT, cytokines stimulate arachidonic acid metabolism → prostaglandin E2 (PGE2) synthesis via cyclooxygenase (COX-2)
5. PGE2 acts on EP3 receptors in the hypothalamus → raises the thermoregulatory set point
6. Hypothalamus signals the vasomotor center → vasoconstriction begins
7. The patient feels cold (blood shunted to internal organs, heat loss from skin decreases)
8. Shivering begins (increases muscle heat production)
9. Behavioral changes (putting on clothes, curling up) conserve heat
10. Core temperature rises until it matches the new set point → patient now feels warm (flushed, hot)
11. When fever "breaks" (defervescence): set point returns to normal → vasodilation, sweating - the patient feels hot and sweats

"The febrile response is characterized by heat conservation (vasoconstriction) and increased heat production (shivering and nonshivering thermogenesis)." - Harrison's 22e

Role of PGE2:

• PGE2 is the final common mediator of fever
• This is why NSAIDs and aspirin (which inhibit COX) are effective antipyretics
• Glucocorticoids reduce fever by inhibiting phospholipase A2 (blocking arachidonic acid release) AND by inhibiting cytokine transcription

4. FEVER PATTERNS (Pyrexia Types)

5. BENEFICIAL EFFECTS OF FEVER

• Inhibits growth of some pathogens (many bacteria grow poorly at 39-40°C)
• Augments T-cell proliferation and neutrophil killing
• Increases acute-phase reactant production (CRP, fibrinogen, complement)
• Impairs viral replication
• Activates natural killer (NK) cells

"Moderate fevers caused by most infectious agents (38-40°C) appear to be beneficial rather than harmful to the host." - Harrison's 22e

6. HARMFUL EFFECTS OF FEVER

• Febrile convulsions in children (6 months to 5 years)
• Increased metabolic demand (~13% increase per 1°C rise) → worsens cardiac/respiratory disease
• Dehydration
• Delirium in elderly
• Fetal damage (>39°C) in pregnancy - especially in 1st trimester (neural tube defects)
• At >41°C: protein denaturation, organ damage (like hyperthermia)

7. CLINICAL FEATURES / ASSESSMENT

History:

• Onset, duration, pattern
• Associated symptoms (rigors, sweating, headache, myalgia, rash)
• Recent travel, animal contact, sexual history
• Medications (drug fever)
• Immunization status
• Occupational exposure

On Examination:

• Vital signs + temperature method (rectal preferred for accuracy in ICU)
• Lymphadenopathy
• Hepatosplenomegaly
• Rash (see below)
• Signs of infection source (chest, abdomen, ENT, skin, IV sites)
• Heart murmurs (endocarditis)
• Joint swelling

8. FEVER AND RASH - Classification (Harrison's 22e, Chapter 18)

9. FEVER OF UNKNOWN ORIGIN (FUO)

Definition (Updated Petersdorf criteria):

1. Fever ≥38.3°C (≥101°F) on at least 2 occasions
2. Illness duration ≥3 weeks
3. No known immunocompromised state
4. No diagnosis despite a minimum basic diagnostic workup

Categories of FUO:

From Harrison's 22e Table 22-1: Infections (median 17% in Western Europe, 44% in Asia), Inflammatory diseases (median 22%), Malignancy (median 7%), No diagnosis (median 45% in Europe vs 22% in Asia)

Workup of FUO:

• CBC with differential, ESR, CRP, LFTs, urinalysis, urine culture
• Blood cultures (x3, aerobic and anaerobic)
• Chest X-ray
• Mantoux/IGRA for TB
• HIV serology, EBV, CMV titres
• ANA, RF, ANCA
• Serum protein electrophoresis

• CT chest/abdomen/pelvis (most productive single investigation for FUO)
• Echocardiography (endocarditis)
• Bone marrow biopsy (lymphoma, disseminated TB/histoplasmosis)
• PET-CT (increasingly used - highlights metabolically active lesions)
• Liver biopsy (granulomatous disease)
• Temporal artery biopsy (elderly patients - giant cell arteritis)

10. ANTIPYRETIC TREATMENT

Indications for treating fever:

• Fever >40°C (regardless of cause)
• Febrile convulsions (or risk thereof in children)
• Cardiac/respiratory compromise
• Pregnancy >38.5°C (fetal risk)
• Patient discomfort
• Elderly with delirium

Agents:

Physical measures:

• Tepid sponging (lukewarm water - NOT cold/ice, which causes shivering and increases temperature)
• Remove excess clothing/bedding
• Fan cooling
• Note: Physical cooling ALONE is insufficient for fever (works best in hyperthermia)

11. SPECIAL SITUATIONS

Fever in the neutropenic patient (Neutropenic Fever):

• Defined as single oral temperature ≥38.3°C OR temperature ≥38°C for >1 hour in a patient with ANC <500 cells/μL (or <1000 cells/μL predicted to fall to <500)
• Medical emergency - empirical broad-spectrum antibiotics must be started within 1 hour
• Coverage: antipseudomonal beta-lactam (piperacillin-tazobactam, cefepime, or carbapenem)
• Risk-stratified by MASCC score

Drug Fever:

• Occurs 7-10 days after starting a new drug
• Characteristics: Relative bradycardia, rash (may be absent), eosinophilia
• Common culprits: antibiotics (especially beta-lactams, sulfonamides), allopurinol, phenytoin, procainamide, quinidine
• Resolves 2-3 days after stopping the offending drug

Factitious Fever:

• Patients self-induce fever (thermometer manipulation, self-injection of pyrogens)
• Suspect: nurses/healthcare workers, inconsistent temperature recordings, no diurnal variation, simultaneous rectal and oral temperatures both taken - they should differ

12. FEVER IN SPECIAL POPULATIONS

13. IMPORTANT MNEMONICS

• M - Malignancy (lymphoma, leukemia, RCC)
• I - Infection (TB, endocarditis, abscess)
• N - Non-infectious Inflammatory disease (SLE, Still's, vasculitis)
• T - Miscellaneous (drug fever, factitious, thyroid)

• IL-1, IL-6, TNF, IFN

QUICK REFERENCE SUMMARY TABLE

Note on Macleod's: Macleod's Clinical Examination is primarily a physical examination and history-taking guide (not a pathophysiology/medicine textbook). For the full fever topic in MBBS medicine, Harrison's (above) is the standard reference. The content above covers all key Macleod's-relevant clinical assessment points (history, examination approach) alongside the full physiological and clinical medicine content.