Fever - Point-wise Notes (Harrison's Principles of Internal Medicine, 22nd Ed., 2025)

1. DEFINITION OF FEVER

• Normal mean oral temperature: 36.6°C (97.9°F); 99th percentile for healthy adults = 37.7°C (99.9°F)
• Fever defined as: temperature >37.7°C (>99.9°F) based on a study of 35,000 individuals
• Fever = elevation of body temperature exceeding normal daily variation, occurring with an increase in the hypothalamic set point
• Distinguished from hyperthermia, which is an uncontrolled rise without change in set point

2. PHYSIOLOGIC VARIATIONS IN BODY TEMPERATURE

• Diurnal rhythm: Low at 8 A.M., peaks at 4 P.M.
• Seasonal variation: Lower in summer, higher in winter
• Rectal temperature: ~0.4°C (0.7°F) higher than oral
• Tympanic (unadjusted mode): ~0.8°C (1.6°F) lower than rectal
• Age: Temperature decreases by 0.02°C per 10-year increase in age
• Menstrual cycle: A.M. temperature rises ~0.6°C (1°F) at ovulation and stays elevated until menses
• Higher ambient temperature → higher baseline body temperature
• Comorbidities: Cancer → +0.02°C; hypothyroidism → -0.01°C
• A rise of 0.15°C (1 SD) in baseline temperature correlates with a 0.52% increase in 1-year mortality

3. FEVER vs. HYPERTHERMIA

• Causes of hyperthermia: heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, drugs that block sweating
• Hyperpyrexia: temperature >41.5°C (>106.7°F) - can occur in severe infections and CNS bleeds

4. PATHOGENESIS OF FEVER

A. Pyrogens

• Microbial products, toxins, whole microorganisms
• Classic example: Lipopolysaccharide (LPS / endotoxin) of gram-negative bacteria
  • As little as 2-3 ng/kg IV produces fever, leukocytosis, acute-phase proteins, and malaise
• Gram-positive organisms: less pyrogenic cell walls, but produce superantigen toxins
  • Staphylococcal TSST-1, enterotoxins; streptococcal pyrogenic exotoxins
  • Cause fever at 1-10 μg/kg IV in animals

B. Pyrogenic Cytokines (Endogenous Pyrogens)

• Small proteins (molecular mass 10,000-20,000 Da)
• Key pyrogenic cytokines:
  • IL-1 (α and β) - fever at 10-100 ng/kg
  • IL-6 - fever at higher doses (1-10 μg/kg)
  • TNF (tumor necrosis factor) - fever at 10-100 ng/kg
  • Ciliary neurotrophic factor (IL-6 family)
  • Interferon-α (fever as prominent side effect in therapy)
• Produced by monocytes, macrophages, endothelial cells, etc. in response to exogenous pyrogens or sterile stimuli (e.g., antigen-antibody complexes, complement)

C. Mechanisms: From Cytokines to Fever

1. Pyrogenic cytokines reach the hypothalamic thermoregulatory center (anterior hypothalamus - organum vasculosum laminae terminalis, OVLT)
2. Stimulate local arachidonic acid metabolism → prostaglandin E2 (PGE2) synthesis via cyclooxygenase (COX)
3. PGE2 acts on EP3 receptors in the preoptic area → raises the set point
4. cAMP is the intracellular mediator in hypothalamic neurons
5. Vasomotor center activated → vasoconstriction → reduced heat loss → person feels cold
6. Shivering increases heat production from muscles
7. Non-shivering thermogenesis from liver contributes
8. Behavioral responses (putting on clothing, curling up) reduce heat loss
9. When set point is lowered (antipyretics or resolution): vasodilation + sweating ("breaking the fever")

D. Endogenous Antipyretics

• Arginine vasopressin (AVP): acts via V1 receptors in the ventral septal area
• α-Melanocyte-stimulating hormone (α-MSH)
• Glucocorticoids: inhibit cytokine synthesis and PGE2 production
• These limit the magnitude and duration of the febrile response

5. BENEFICIAL EFFECTS OF FEVER

• Fever is not merely a symptom - it is a host defense response
• Enhances neutrophil and macrophage activity
• Augments T-lymphocyte proliferation
• Increases interferon efficacy
• Inhibits bacterial and viral replication (many pathogens are temperature-sensitive)
• Stimulates acute-phase protein synthesis (CRP, fibrinogen, serum amyloid A)
• Acute-phase response mediated primarily by IL-6

6. TREATMENT OF FEVER

When to Treat

• Antipyretics are not always necessary - fever may be beneficial
• Treatment recommended when:
  • Fever causes significant discomfort (headache, myalgia, dehydration)
  • Risk of febrile seizures (children 6 months - 5 years)
  • Patients with heart disease, pulmonary insufficiency (increased O2 demand)
  • Pregnancy (hyperthermia is teratogenic)
  • Fever >41°C with potential organ damage

Antipyretic Drugs

• All antipyretics work by inhibiting PGE2 synthesis in the hypothalamus
• In hyperthermia, antipyretics are ineffective - active cooling is required
• Physical cooling (sponging, cooling blankets) is adjunctive and useful in hyperpyrexia

7. FEVER PATTERNS (Clinical Importance)

• Intermittent fever: Temperature returns to normal each day (e.g., pyogenic abscess, Gram-negative bacteremia)
• Remittent fever: Temperature never returns to normal, fluctuates >1°C daily (e.g., typhoid, brucellosis)
• Sustained / Continuous fever: Persistent elevation with <0.3°C variation (e.g., lobar pneumonia, rickettsial disease)
• Relapsing fever: Recurring episodes separated by afebrile periods (e.g., Borrelia, malaria, Pel-Ebstein fever in Hodgkin's)
• Pel-Ebstein fever: Cyclical pattern (days of fever alternating with days of normal/subnormal temp) - associated with Hodgkin's lymphoma
• Factitious fever: Temperature elevation induced by the patient themselves (important in FUO workup)

8. FEVER OF UNKNOWN ORIGIN (FUO)

Definition (Current Standard)

1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Illness duration ≥3 weeks
3. No known immunocompromised state

• Original Petersdorf & Beeson (1961) definition also required 1 week of inpatient evaluation; modern definitions allow outpatient workup

Epidemiology

• Prevalence largely unknown; varies by geography
• Chance of remaining undiagnosed is 2-5× higher in Europe vs. Asia

Etiology (Four Major Categories)

FUO Workup Approach

• CBC, differential, ESR, CRP, metabolic panel, LFTs, urinalysis + culture
• Blood cultures ×3, CXR, ANA, RF, ANCA
• HIV, EBV, CMV serology; TB testing (TST/IGRA)
• CT chest/abdomen/pelvis
• Echocardiogram (if endocarditis suspected)

• 18F-FDG-PET/CT: most powerful imaging tool for FUO; identifies sites of inflammation/malignancy; normal PET/CT predicts higher rate of spontaneous resolution
• Bone marrow biopsy (if hematologic malignancy or disseminated infection suspected)
• Temporal artery biopsy (in elderly with elevated ESR)
• Molecular diagnostics (next-generation sequencing, metagenomics)

Treatment of FUO

• Empirical antibiotics: Only for critically ill patients; should not be used routinely as they obscure diagnosis
• Empirical glucocorticoids: Impressive effect in giant cell arteritis/PMR; avoid until infection and lymphoma sufficiently excluded - can mask fever while permitting spread
• Anakinra (IL-1 receptor antagonist): Consider in FUO with signs of IL-1-driven inflammation (serositis, elevated CRP, elevated ferritin); effective in Still's disease, FMF, cryopyrin-associated periodic syndromes; preferred over glucocorticoids for autoinflammatory conditions

Prognosis of FUO

• Depends on underlying etiology
• In patients remaining undiagnosed: mortality ≤8% in large cohort studies over several years
• High rate of spontaneous resolution when no diagnosis is found
• Normal 18F-FDG-PET/CT associated with higher rates of spontaneous resolution

9. SPECIAL SITUATIONS

Fever in the Elderly

• Baseline temperature is lower (-0.02°C per decade)
• May present with relative hypothermia even with serious infection
• Giant cell arteritis and PMR are important FUO causes in this group

Fever and Rash

• Pattern of rash + fever narrows diagnosis significantly:
  • Petechiae/purpura: Meningococcemia, RMSF, DIC - life-threatening emergency
  • Maculopapular: Viral exanthems, drug reactions, typhoid, rickettsial disease
  • Vesicular: Herpes zoster, primary varicella, HSV, hand-foot-mouth disease
  • Erythema migrans: Lyme disease

Neutropenic Fever

• Defined as single temperature ≥38.3°C OR ≥38°C for ≥1 hour in a patient with ANC <500/μL (or expected to fall below 500)
• Requires immediate empirical broad-spectrum antibiotics (e.g., piperacillin-tazobactam, cefepime, or carbapenem)
• Risk stratification: MASCC score (low vs. high risk)
• High-risk: ANC <100, mucositis, hemodynamic instability, >7 days duration expected → hospitalize + IV antibiotics

10. KEY PHARMACOLOGY POINTS

• Aspirin and NSAIDs: irreversibly (aspirin) or reversibly inhibit COX → reduce arachidonic acid → reduce PGE2
• Glucocorticoids: inhibit phospholipase A2 (block arachidonic acid release) AND inhibit cytokine gene transcription
• Anakinra: recombinant IL-1Ra; blocks both IL-1α and IL-1β; highly effective in autoinflammatory FUO
• Antipyretics do NOT affect the course of infection in most viral illnesses - they only reduce discomfort

11. SUMMARY TABLE: KEY NUMBERS TO REMEMBER

What's Included (14 Sections):

1. Normal Body Temperature - definitions, physiological variations, measurement sites, clinical significance
2. Fever vs. Hyperthermia - complete comparison table, mechanism of each, hyperpyrexia definition
3. Pathogenesis of Fever - with the original Fig. 20-1 flowchart showing the complete cascade from infection → IL-1/IL-6/TNF → PGE2 → cAMP → set-point elevation → fever
4. Exogenous Pyrogens - LPS, gram-positive superantigen toxins, exact fever-inducing doses
5. Pyrogenic Cytokines - IL-1, IL-6, TNF, IFN-α with human fever doses
6. Hypothalamic Set-Point Mechanism - step-by-step: OVLT, COX, PGE2, EP-3 receptor, cAMP
7. Endogenous Antipyretics - AVP, α-MSH, glucocorticoids
8. Beneficial Effects of Fever - immune enhancement, acute-phase proteins
9. Clinical Approach - history, PE, lab workup, blunted fever states, anticytokine therapy
10. Fever Patterns - intermittent, remittent, Pel-Ebstein, malaria, relapsing fever
11. Fever and Rash - with clinical image; all rash types and diagnoses
12. Treatment - when to treat, mechanisms of antipyretics, anakinra for autoinflammatory disease
13. FUO - definition, etiology table, four categories (with VEXAS syndrome), complete diagnostic algorithm with Fig. 22-1 flowchart and Fig. 22-2 FDG-PET/CT example
14. Quick Reference Numbers - all key values in one table

What's Covered (25 Sections across 6 Chapters):

Part I - Pain Pathophysiology & Management (Ch. 14)

• Pain sensory system - duality, stress response, protective function
• Peripheral mechanisms - Aβ/Aδ/C fiber types (with Fig. 14-1), TRPV1 receptor, what activates nociceptors
• Sensitization - mechanism, mediators (BK, NGF, PGs, leukotrienes), silent nociceptors
• Neurogenic inflammation - Substance P, CGRP, mast cell/platelet activation (with Fig. 14-2)
• Central mechanisms - glutamate, Substance P, referred pain via convergence-projection (with Fig. 14-3), spinothalamic tract
• Descending modulation - PAG → RVM → dorsal horn inhibition; opioid and placebo analgesia (with Fig. 14-4)
• Types of pain - nociceptive, inflammatory, neuropathic, nocipastic, mixed
• Pharmacology - NSAIDs, opioids, TCAs, SNRIs, anticonvulsants, cannabinoids

Part II - Chest Discomfort (Ch. 15)

• Ischemia/ACS classification, angina characteristics, atypical presentations
• Aortic dissection, PE, pericarditis, esophageal, musculoskeletal causes
• ECG patterns, high-sensitivity troponin protocols, imaging

Part III - Abdominal Pain (Ch. 16)

• Visceral vs. parietal vs. referred pain mechanisms
• Complete differential by quadrant (Table 16-3)
• Surgical emergencies, physical examination principles, investigation strategy

Part IV - Headache (Ch. 17)

• Red flags (SNOOP), secondary headaches (meningitis, SAH, brain tumor, GCA)
• Primary headaches: migraine (pathophysiology, CGRP, triptans, gepants, anti-CGRP MAbs), tension-type, cluster headache, CDH/MOH

Part V - Low Back Pain (Ch. 18)

• Myofascial, discogenic, radicular, stenosis, nocipastic pain; nerve root levels (L3-S1)
• Red flags, biopsychosocial model, pharmacotherapy (evidence-based), psychological therapies

Part VI - Neck Pain (Ch. 19)

• Epidemiology, anatomy (C1-C2 = 50% motion), cervical radiculopathy levels (C5-T1)
• Spurling's test, Lhermitte's sign, dangerous causes (myelopathy, epidural abscess, dissection)

Complete Coverage Summary:

Chapter 14 — Pain Pathophysiology & Management

• Pain duality, stress response, Aβ/Aδ/C fibers with Fig. 14-1 (nerve anatomy image)
• TRPV1, capsaicin, all nociceptor activators
• Sensitization, silent nociceptors, neurogenic inflammation (Substance P, CGRP) with Fig. 14-2 (primary vs. secondary activation image)
• Referred pain, convergence-projection with Fig. 14-3 (visceral-somatic convergence image)
• Spinothalamic tract, thalamus, cortical targets
• Descending modulation: PAG → RVM → dorsal horn, opioidergic circuit with Fig. 14-4 (ascending + modulation pathways image)
• Pain type classification table (nociceptive/neuropathic/nocipastic/mixed)
• Full drug table with dosages: NSAIDs (aspirin 650mg, ibuprofen 450mg, naproxen 250-500mg, ketorolac 15-30mg), opioids (codeine, tramadol, oxycodone, morphine, hydromorphone, fentanyl, methadone, buprenorphine), TCAs (nortriptyline/desipramine/amitriptyline with doses), SNRIs, anticonvulsants (gabapentin 900-3600mg/day, pregabalin 150-600mg/day, carbamazepine), cannabinoids, interventional procedures

Chapter 15 — Chest Discomfort

• ACS classification, ischemic pain characteristics, atypical presentations
• Aortic dissection, PE, pericarditis, esophageal, musculoskeletal
• Full ECG interpretation table, high-sensitivity troponin protocols (serial at 1-3h vs 3-6h), imaging guide

Chapter 16 — Abdominal Pain

• Three mechanisms: visceral vs. parietal vs. referred (with rate-of-exposure detail)
• Hollow viscus obstruction mechanisms
• Full differential by quadrant table (RUQ/epigastric/LUQ/RLQ/LLQ/periumbilical/diffuse)
• Toxic and neurogenic causes (lead, spider bite, narcotic withdrawal)
• Examination principles ("do not be brusque"), gentle percussion vs. rebound, cough test
• Investigation guide (CT, ultrasound, HIDA, laparoscopy, contrast enema rules)

Chapter 17 — Headache

• Full headache anatomy (pain-sensitive vs. non-pain-sensitive structures)
• IHS classification table (primary 69% tension-type, 16% migraine etc.)
• Red flags table (12 symptoms, all listed)
• Secondary headaches: meningitis, SAH (thunderclap), intracranial hemorrhage, brain tumor, GCA with all clinical details
• Migraine: phases (premonitory/aura/headache/resolution/postdrome), CSD mechanism, CGRP role, ICHD criteria
• Complete acute migraine drug table: all 7 triptans with doses, gepants (ubrogepant 50-100mg, rimegepant 75mg), lasmiditan, DHE, ergotamine, metoclopramide, prochlorperazine, ketorolac
• Complete migraine prevention table: propranolol 80-240mg, topiramate 50-100mg, valproate 500-1500mg, amitriptyline, candesartan, all 4 anti-CGRP MAbs (erenumab/fremanezumab/galcanezumab/eptinezumab) with dosages, atogepant, onabotulinumtoxinA (155-195 units q12 weeks - chronic migraine only)
• Tension-type headache: criteria + treatment
• Cluster headache: criteria, autonomic features table, 100% O2 15L/min, sumatriptan 6mg SC, verapamil 240-960mg/day, MOH

Chapter 18 — Low Back Pain

• Pain categorization table (nociceptive/neuropathic/nocipastic with full clinical characteristics)
• Myofascial, discogenic, facet, SI joint, radicular, spinal stenosis (neurogenic vs. vascular claudication table), spondylolisthesis
• Nerve root levels L3-S1 (pain/motor/reflex)
• Red flags table (10 flags with diagnoses and actions)
• Full physical examination guide (Spurling, SLR sensitivity/specificity, femoral stretch, Waddell signs)
• Full pharmacotherapy table with dosages: NSAIDs, cyclobenzaprine 5-10mg TID, tizanidine 2-4mg TID, duloxetine 30→120mg/day, TCAs, tramadol 50-100mg q6h
• Psychological comorbidities (depression 33-67%, anxiety 10-30%)

Chapter 19 — Neck Pain

• Full anatomy (C1-C2 = 50% of rotation), risk factors
• Red flags, Spurling's maneuver, Lhermitte's sign, Hoffman sign, ULTT
• Cervical radiculopathy table C3-T1 (pain/sensation/motor/reflex)
• Comprehensive etiology table (whiplash = 50% persistent at 1 year; myelopathy details)
• Drug dosage table: cyclobenzaprine 5-10mg qhs, NSAIDs, radiofrequency ablation indications
• Master quick-reference drug table at the end (all 30+ drugs with doses, indications, key risks)