GC048 Fever
Fever is an elevation of body temperature above the normal range, typically exceeding 38°C (100.4°F), resulting from a resetting of the hypothalamic thermoregulatory set point in response to pyrogenic stimuli.
Fever — GC 048 Comprehensive Exam-Ready Notes
This lecture (GC 048, Dr. Tommy Cheung, Department of Medicine) is the foundational framework for approaching any febrile patient. It covers the physiology of normal body temperature, the mechanism by which fever arises (distinct from hyperthermia), the systematic causes of fever, and – critically for exams – the definition, differential diagnosis, and workup of Pyrexia of Unknown Origin (PUO/FUO). This lecture connects to virtually every other GC session: fever after travelling (GC 103), fever after chemotherapy (GC 102), fever after blood transfusion (GC 049), fever and confusion (GC 051), fever and purulent sputum (GC 052), URTI (GC 021), and immunodeficiency (GC 096).
Learning Objectives (directly from the lecture): [1]
- Definition of fever
- Mechanisms of fever
- Causes of fever
- Definition of Pyrexia of Unknown Origin
- Differential diagnosis of PUO
- Workup for PUO
1. Normal Body Temperature
You cannot define "fever" without first knowing what is "normal." Examiners love threshold numbers. Also, the site of measurement determines the threshold — a common trap.
In healthy adults, normal temperature varies at different sites of measurement [1]
| Site | Normal Range | Why Different |
|---|---|---|
| Oral | 33.2–38.2°C | Accessible but affected by recent drinks, mouth-breathing |
| Rectal | 34.4–37.8°C | Closest to core temperature; gold standard in paediatrics |
| Tympanic | 35.4–37.8°C | Reflects hypothalamic blood supply via internal carotid; quick but operator-dependent |
| Axillary | 35.5–37.0°C | Least invasive but least accurate; typically ~0.5°C lower than core |
Normal temperature also depends on age, sex, time of measurement, activity level, etc. [1]
- Diurnal variation: Lowest in early morning (~06:00), peaks in late afternoon (~16:00–18:00). This variation is typically ≤ 1°C and is governed by the circadian rhythm of cortisol and melatonin.
- Age: Elderly patients may have a lower baseline and can be significantly infected without mounting a high fever.
- Sex: Women tend to have slightly higher temperatures, especially in the luteal phase of the menstrual cycle (progesterone raises the set point by ~0.3–0.5°C).
- Activity/exercise: Vigorous activity transiently raises core temperature.
Exam Trap
Don't confuse the normal range with the fever threshold. The normal range is broad, but the threshold for "fever" is a specific cut-off at each site (see Section 2).
The hypothalamic thermoregulatory centre (specifically the preoptic area of the anterior hypothalamus) acts as the body's thermostat. It receives input from:
- Peripheral thermoreceptors (skin — detecting ambient temperature)
- Central thermoreceptors (blood temperature flowing through the hypothalamus itself)
When body temperature deviates from the set point (~37°C), effector mechanisms are activated:
| Too Hot (need to lose heat) | Too Cold (need to conserve/generate heat) |
|---|---|
| Cutaneous vasodilation | Cutaneous vasoconstriction |
| Sweating | Shivering (involuntary skeletal muscle contraction) |
| Behavioural (seeking shade, removing clothes) | Behavioural (seeking warmth, adding clothes) |
| Decreased metabolic rate | Increased metabolic rate (brown fat thermogenesis in neonates) |
Key concept: In fever, the set point itself is raised. The body "thinks" it is too cold relative to the new set point, so it activates heat-conserving mechanisms (vasoconstriction → chills/rigors, shivering). This is fundamentally different from hyperthermia.
Fever is defined at different thresholds depending on site: [1]
| Site | Fever Threshold |
|---|---|
| Oral | ≥ 37.8°C |
| Rectal | ≥ 38.0°C |
| Tympanic | ≥ 38.0°C |
| Axillary | ≥ 37.2°C |
High Yield — Hyperpyrexia
Hyper-pyrexia is defined as core temperature > 40°C. [1]
- Indicates a serious underlying condition
- May lead to permanent brain damage
This is a commonly tested definition. At > 40°C, protein denaturation begins, cellular enzyme function is impaired, and CNS damage becomes a real risk.
Paediatric note (for integration)
In infants ≤ 90 days old, a rectal temperature ≥ 38°C is the gold standard definition of fever. This corresponds to 2 standard deviations above the mean for this age group. [5]
Fever involves a change in the hypothalamic set point and involves cytokines (IL-1, IFN, and TNF-α) [1]
Step-by-step from first principles:
- Trigger: Exogenous pyrogens (bacterial products like LPS/endotoxin, viral particles, fungal wall components) are detected by immune cells (monocytes, macrophages, neutrophils).
- Endogenous pyrogen release: These immune cells release endogenous pyrogens = pro-inflammatory cytokines:
- IL-1 (interleukin-1)
- TNF-α (tumour necrosis factor alpha)
- IL-6 (interleukin-6)
- IFN (interferons)
- Prostaglandin E2 (PGE2) synthesis: These cytokines act on vascular endothelium near the hypothalamus (specifically at the organum vasculosum of the lamina terminalis, OVLT — a circumventricular organ lacking a blood-brain barrier). They induce cyclooxygenase-2 (COX-2), which converts arachidonic acid → PGE2.
- Set-point elevation: PGE2 binds to EP3 receptors on thermoregulatory neurons in the preoptic area → raises the set point.
- Effector response: Body perceives current temperature as "too cold" → triggers shivering, vasoconstriction, behavioural warmth-seeking → temperature rises to the new set point.
- Defervescence: When cytokine levels drop (infection cleared, or antipyretics given), set point returns to normal → body now perceives itself as "too hot" → sweating, vasodilation → temperature falls.
Why this matters clinically: NSAIDs and paracetamol work as antipyretics by inhibiting COX → reducing PGE2 → lowering the set point. They work in fever but NOT in hyperthermia (because hyperthermia does not involve a set-point change).
This distinction is directly from the lecture and is a classic exam question [1]
| Feature | Fever | Hyperthermia |
|---|---|---|
| Mechanism | Change in hypothalamic set point | Failure in thermoregulation |
| Mediators | Involves cytokines (IL-1, IFN, TNF-α) | No cytokine involvement |
| Diurnal variation | Usually preserved | Absent |
| Response to antipyretics | Yes (NSAIDs/paracetamol lower set point) | No (set point is normal; problem is excess heat production or inadequate dissipation) |
| Upper ceiling | Usually self-limited (rarely > 41°C) | Can exceed 41°C; no physiological brake |
| Examples | Infections, autoimmune, malignancy | Heatstroke, malignant neuroleptic syndrome, serotonin syndrome, thyroid storm |
Critical Distinction
Fever = set point UP (regulated). Hyperthermia = thermoregulation FAILS (unregulated). Treat hyperthermia with physical cooling (ice packs, evaporative cooling), NOT antipyretics. Antipyretics are useless in hyperthermia because PGE2 is not the problem.
Examples of Hyperthermia (from lecture) [1]:
- Heatstroke: Environmental heat exceeds the body's ability to dissipate. Classic (elderly in heatwave) vs. exertional (athletes).
- Neuroleptic Malignant Syndrome (NMS): Idiosyncratic reaction to dopamine antagonists (antipsychotics like haloperidol). Features: hyperthermia, rigidity, altered consciousness, autonomic instability, elevated CK. Treatment: dantrolene, cooling, stop offending drug.
- Serotonin Syndrome: Excess serotonergic activity (SSRIs, MAOIs, tramadol, linezolid combinations). Features: hyperthermia, clonus, hyperreflexia, agitation, diaphoresis. Treatment: cyproheptadine, cooling, stop offending drug.
- Thyroid Storm: Extreme thyrotoxicosis. Features: hyperthermia, tachycardia, altered consciousness, GI symptoms. Treatment: beta-blockers, PTU/carbimazole, iodine, hydrocortisone.
- Malignant Hyperthermia: Genetic (often RYR1 mutation); triggered by volatile anaesthetics (halothane, sevoflurane) or succinylcholine. Massive uncontrolled skeletal muscle contraction → heat. Treatment: dantrolene.
Fever patterns are a classic lecture slide and frequently tested [1]
| Pattern | Description | Causes |
|---|---|---|
| Continuous | Temperature does not fluctuate > 1°C (remains elevated throughout) | Pyrogenic infections, dengue fever, fungal infections |
| Remittent | Temperature remains above normal but fluctuates > 1°C | Infective endocarditis, brucellosis, typhoid fever |
| Intermittent | Elevation of temperature is present only for a certain period (returns to normal between spikes) | Malaria, tuberculosis, Lyme disease, borreliosis, EBV |
Additional patterns worth knowing (for integration):
- Quotidian: Daily fever spikes (e.g. P. falciparum malaria, Adult-onset Still's disease — classically double quotidian with "salmon-coloured" evanescent rash)
- Tertian: Every 48 hours (P. vivax, P. ovale)
- Quartan: Every 72 hours (P. malariae)
- Pel-Ebstein: Periodic fever lasting 1–2 weeks alternating with afebrile periods of 1–2 weeks — classically described in Hodgkin lymphoma (rarely seen clinically)
- Saddle-back fever: Fever that drops then returns — dengue
Exam Tip — Typhoid Fever
Typhoid fever classically shows a "stepladder" rise in temperature during the first week, becoming remittent/continuous in weeks 2–3. The 2019 minicase directly tested this: a 23-year-old returning from Bangladesh with high fever (40°C), pulse 50 bpm (relative bradycardia = Faget's sign, pathognomonic clue for typhoid), rose spots on chest/abdomen, and constipation → diarrhoea. [3]
6. Causes of Fever — Systematic Classification
The lecture categorises causes of fever into 6 major groups [1]
| Category | Conditions | Why Fever Occurs |
|---|---|---|
| Infections | Virus, bacteria, fungus, parasite | Exogenous pyrogens (microbial products) → cytokine release → PGE2 |
| Autoimmune diseases | SLE, Adult Still's disease, Giant cell arteritis, Sarcoidosis | Chronic immune activation → persistent cytokine release |
| Malignancies | Lymphoma, leukaemia, renal cell carcinoma | Tumour cells produce cytokines (IL-6, TNF-α) directly; tumour necrosis releases pyrogens |
| Tissue destruction | Massive infarction, massive haemolysis, rhabdomyolysis | Necrotic tissue releases intracellular contents → inflammatory response |
| Metabolic disorders | Gout, porphyria | Crystal deposition (gout: urate crystals) → inflammasome activation → IL-1β release |
| Drugs | Antibiotics, anticonvulsants | Multiple mechanisms (see Drug Fever section below) |
Infections account for the majority of acute fevers because microbial products (endotoxins, exotoxins, peptidoglycans, viral nucleic acids) are potent activators of innate immunity → massive cytokine release.
- Lymphoma (especially Hodgkin and aggressive NHL): Lymphoma cells secrete IL-6 and TNF-α directly. B symptoms (fever, night sweats, weight loss) are part of staging.
- Leukaemia: Blast cells release cytokines; also predisposes to infections through neutropenia.
- Renal cell carcinoma: Classic "internist's tumour" — frequently presents with paraneoplastic fever, often the only presenting symptom. Produces IL-6, erythropoietin, PTHrP.
When cells undergo massive necrosis (e.g., myocardial infarction, crush injury/rhabdomyolysis, haemolysis), intracellular contents (DAMPs — damage-associated molecular patterns like HMGB1, heat shock proteins, uric acid) are released → activate innate immune receptors (TLRs, NLRP3 inflammasome) → cytokine release → fever.
7. Drug Fever — Detailed Mechanisms
The lecture classifies drug fever into 4 mechanisms [1]
- Most common mechanism of drug fever
- Type I (IgE-mediated): Immediate; anaphylaxis, urticaria, angioedema. Fever less prominent.
- Type II (cytotoxic): Drug-induced haemolytic anaemia, thrombocytopenia.
- Type III (immune complex): Serum sickness-like reaction (fever, rash, arthralgia, lymphadenopathy). Classic example: beta-lactam antibiotics.
- Type IV (delayed/cell-mediated): DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms). Onset 2–8 weeks after drug initiation. Fever + morbilliform rash + eosinophilia + organ involvement (liver, kidney).
- Common culprits: antibiotics (beta-lactams, sulfonamides), anticonvulsants (phenytoin, carbamazepine, lamotrigine).
- Exogenous thyroid hormone (excess → raises metabolic rate → heat production)
- Drugs with anticholinergic activities (block sweating → cannot dissipate heat)
- Sympathomimetic agents (increase metabolic rate, vasoconstriction → heat retention)
Drug's intended action at suprapharmacological doses causes temperature elevation (e.g., chemotherapy → tumour lysis → tissue destruction → fever).
- Malignant hyperthermia (volatile anaesthetics, succinylcholine)
- Neuroleptic malignant syndrome (antipsychotics)
- Serotonin syndrome (serotonergic drugs)
Surgical Relevance — Post-op Fever
The surgical "5 W's" mnemonic for post-operative fever (Wind, Water, Wound, Walking, Wonder drugs) is directly relevant. "Wonder drugs" = drug fever, typically appearing 7–10 days post-op, fitting the Type IV hypersensitivity timeline. [2]
8. Pyrexia of Unknown Origin (PUO / FUO)
This is the centrepiece of the lecture and a perennial exam favourite.
PUO is defined as:
- Fever > 38.3°C on several occasions
- Duration > 3 weeks
- Unable to reach a diagnosis despite 1 week of inpatient investigation
Why these criteria?
- 38.3°C: High enough to exclude trivial/self-limiting febrile illnesses.
- 3 weeks: Eliminates most acute viral infections (which self-resolve in 1–2 weeks).
- 1 week of inpatient investigation: Ensures basic workup (bloods, cultures, imaging) has been done and the case is genuinely puzzling.
High Yield Definition
Memorise the three criteria verbatim — they are directly tested in MCQs and SAQs. The temperature threshold for PUO (38.3°C) is higher than the standard fever definition (37.8°C oral).
| Category | Definition |
|---|---|
| Classical PUO | As above (community-acquired, immunocompetent) |
| Nosocomial PUO | Hospitalised patient, fever developing ≥ 3 days after admission, no infection present on admission |
| Neutropenic PUO | ANC ≤ 500/µL + fever, no diagnosis after 3 days investigation |
| HIV-associated PUO | HIV-positive patient, fever > 4 weeks (outpatient) or > 3 days (inpatient) |
The lecture shows evolving data from 1913–2005 demonstrating a shift in PUO causes [1]
| Category | Key Conditions | Trend Over Time |
|---|---|---|
| Infections | Abdominal abscess, endocarditis, mycobacterial (TB) | Decreasing proportion in developed countries (better diagnostics) |
| Malignancies | Lymphoma, solid organ tumours | Decreasing (earlier cancer detection with CT/PET) |
| Connective tissue diseases | SLE, vasculitis, Adult Still's disease | Increasing relative proportion |
| Miscellaneous | Drug fever, factitious fever, DVT/PE, thyroiditis, granulomatous conditions | Stable |
| No diagnosis | Despite full workup; generally good prognosis | Increasing (up to 50% in some series) |
Most fevers that persist beyond this period are caused by common conditions presenting uncommonly. [1]
This is a key teaching point: PUO is rarely an exotic disease. It is usually a common disease that has not declared itself yet.
8.4 Specific Causes Worth Highlighting
- Abdominal abscess: Subphrenic, hepatic, pelvic. Often post-surgical. CT abdomen is the key investigation.
- Infective endocarditis: Subacute presentation with low-grade fever, new murmur, splinter haemorrhages. Blood cultures (3 sets from different sites) are essential. Modified Duke criteria for diagnosis.
- Mycobacterial infections (TB): Especially extrapulmonary TB, miliary TB, and cryptic miliary TB in the elderly (insidious, sputum AFB often negative, TST often negative — diagnosis sometimes only at autopsy). [2] Always consider TB in PUO; may warrant empirical anti-TB therapy even without definitive evidence.
- SLE: Young women; malar rash, arthritis, serositis, cytopenias. Check ANA, anti-dsDNA, complement levels.
- Vasculitis: Giant cell arteritis (elderly, headache, jaw claudication, visual symptoms, elevated ESR > 50). Temporal artery biopsy is diagnostic.
- Adult Still's disease: Young adults; quotidian/double-quotidian fever, evanescent salmon-coloured rash, arthritis, sore throat, serositis, markedly elevated ferritin (often > 10,000) with low glycosylated ferritin fraction. Diagnosis of exclusion.
- Lymphoma: Most common malignancy causing PUO. CT, PET-CT, and lymph node biopsy are key.
- Solid tumours: Renal cell carcinoma, hepatocellular carcinoma, atrial myxoma.
9. Diagnostic Approach to PUO
The lecture outlines a stepwise approach: History → Physical Examination → Laboratory Tests → Imaging [1]
- Localising symptoms (any clue to the organ system involved)
- Intake of drugs (drug fever is a diagnosis of exclusion; temporal relationship is key)
- Travel (malaria, typhoid, dengue, rickettsial infections)
- Animal exposure (brucellosis from unpasteurised dairy; Q fever from cattle/sheep; leptospirosis from rat urine)
- Risk of immunosuppression (HIV status, transplant, chemotherapy, biologics → broadens the differential enormously)
Also consider: occupational exposure, sexual history, family history of periodic fever syndromes, recent procedures/surgery.
Directed by history but must be comprehensive and repeated:
- Skin: Rashes (rose spots of typhoid, erythema marginatum of rheumatic fever, Janeway lesions/Osler nodes of endocarditis, livedo reticularis of vasculitis)
- Lymph nodes: Generalised lymphadenopathy (lymphoma, HIV, SLE, sarcoidosis)
- Heart: New murmur (endocarditis)
- Abdomen: Hepatosplenomegaly (infection, lymphoma, haematological malignancy)
- Joints: Swelling, warmth (septic arthritis, gout, reactive arthritis)
- Eyes: Fundoscopy (Roth spots in endocarditis; choroidal tubercles in miliary TB)
- Temporal arteries: Tenderness, reduced pulsation (GCA)
9.3 Laboratory Investigations
Acute Phase Reactants [1]
Factors that increase ESR:
- Age, female sex, pregnancy, anaemia, renal disease
Factors that decrease ESR:
- Red cell abnormalities (e.g. sickle cells, polycythaemia), extreme leukocytosis, hyper-viscosity
Why ESR works: ESR measures how fast RBCs settle in a tube over 1 hour. Acute phase proteins (especially fibrinogen) coat RBCs, neutralise their negative surface charge → increased rouleaux formation → faster sedimentation. Therefore, any condition increasing fibrinogen or other acute phase proteins raises ESR.
Normal ESR rule of thumb:
- Males: Age/2
- Females: (Age + 10)/2
Clinical utility: Extremely elevated ESR (> 100 mm/hr) → consider: multiple myeloma, giant cell arteritis/polymyalgia rheumatica, severe infection (TB, endocarditis), malignancy, SLE.
- Produced by the liver in response to IL-6
- Rises within 6–8 hours of inflammation, peaks at 48 hours, falls rapidly with resolution
- More specific for acute inflammation than ESR (not affected by anaemia, pregnancy, age as much)
- Very high CRP (> 100 mg/L) → strongly suggests bacterial infection
- Useful for monitoring treatment response
- Normally produced by thyroid C cells (precursor of calcitonin)
- In bacterial infection, virtually all tissues can produce PCT in response to bacterial endotoxins and cytokines
- Key discriminator: PCT is elevated in bacterial infections but remains low in viral infections and autoimmune inflammation
| PCT Level | Interpretation |
|---|---|
| < 0.1 ng/mL | Bacterial infection very unlikely |
| 0.1–0.25 ng/mL | Bacterial infection unlikely |
| 0.25–0.5 ng/mL | Bacterial infection possible |
| > 0.5 ng/mL | Bacterial infection likely |
| > 2 ng/mL | Severe bacterial infection / sepsis |
| > 10 ng/mL | Severe sepsis / septic shock |
Clinical application: PCT-guided antibiotic stewardship — can help decide when to start and when to stop antibiotics (especially in lower respiratory tract infections and ICU settings).
Comparison: ESR vs CRP vs PCT
- ESR: Slow to rise, slow to fall. Non-specific. Affected by many non-inflammatory factors. Good for chronic conditions (GCA, PMR, myeloma).
- CRP: Fast rise, fast fall. More specific for active inflammation. Good for monitoring acute infections.
- PCT: Most specific for bacterial infection. Not elevated in viral or autoimmune. Best for antibiotic decision-making.
- CBC with differential: Neutrophilia (bacterial), lymphocytosis (viral, TB), eosinophilia (parasites, drugs, lymphoma), pancytopenia (marrow infiltration, SLE)
- Blood cultures: At least 2–3 sets from different venepuncture sites before antibiotics
- LFT: Hepatic abscess, granulomatous hepatitis
- Urinalysis + urine culture: UTI as occult source
- Autoimmune screen: ANA, anti-dsDNA, ANCA, RF, complement
- LDH: Elevated in lymphoma, haemolysis, tissue destruction
- Ferritin: Markedly elevated in Adult Still's disease, haemophagocytic lymphohistiocytosis (HLH)
- Peripheral blood film: Atypical lymphocytes (EBV), blasts (leukaemia), rouleaux (myeloma)
- HIV serology: Always consider in unexplained persistent fever
9.4 Imaging [1]
Imaging modalities for PUO:
- CT (Computed Tomography)
- MRI (Magnetic Resonance Imaging)
- Gallium scan
- PET-CT (Positron Emission Tomography–CT)
- First-line cross-sectional imaging for PUO workup
- CT thorax/abdomen/pelvis to identify abscesses, lymphadenopathy, solid organ masses, splenomegaly
- Superior soft tissue resolution
- Particularly useful for: CNS infections (brain abscess, encephalitis), spinal infections (spondylodiscitis — tested in 2023 minicase [3]), cardiac (endocarditis vegetation characterisation)
- Gallium-67 citrate accumulates in areas of inflammation/infection and some tumours
- Being largely replaced by PET-CT but still occasionally used
- 18F-FDG PET-CT is increasingly the investigation of choice for PUO workup
- FDG (fluorodeoxyglucose) is taken up by metabolically active cells → inflammatory/malignant foci "light up"
- Advantages: Whole-body survey, can identify occult infections (endocarditis, vascular graft infections), vasculitis (large vessel), lymphoma, and other malignancies
- Sensitivity for identifying the cause of FUO: ~55–90%
- Can guide biopsy (e.g., lighting up lymph node → targeted biopsy)
PET-CT in PUO — Exam Favourite
PET-CT is considered the most useful imaging modality in the workup of PUO when initial investigations are unrevealing. If an exam question asks "What imaging would you order next in a patient with PUO and unremarkable CT?", the answer is PET-CT.
10. Integration: Fever in Special Contexts
- Definition: ANC ≤ 500/µL AND (single oral temperature ≥ 38.3°C OR sustained ≥ 38.0°C for ≥ 1 hour)
- Medical emergency: Blood cultures + empirical broad-spectrum antibiotics (e.g., piperacillin-tazobactam or meropenem) within 1 hour
- Most common organism identified: S. epidermidis (line-related); P. aeruginosa remains the most serious
- Past paper 2021 SAQ Q12 directly tests this [3]
- Febrile non-haemolytic transfusion reaction: Most common; antibodies against donor leukocyte antigens; onset 30 min–2 hr
- ABO-incompatible haemolytic transfusion reaction: IgM anti-A/anti-B → complement activation → intravascular haemolysis → haemoglobinuria (coca-cola urine), shock, DIC
- Bacterial contamination: Especially platelet concentrates (stored at room temperature). Patient becomes severely septic.
- Think: Malaria (any traveller from endemic area with fever is malaria until proven otherwise), typhoid (contaminated food/water), dengue (mosquito-borne), rickettsial infections
- 2019 minicase: Classic typhoid case from Bangladesh — Faget's sign (relative bradycardia), rose spots, stepladder fever [3]
- "5 W's" mnemonic: Wind (atelectasis/pneumonia day 1–3), Water (UTI day 3–5), Wound (SSI day 5–7), Walking (DVT/PE day 5+), Wonder drugs (drug fever day 7–10)
Based on lecture content, past papers (2019–2025), and common exam patterns:
| Question Type | Likely Stem | Key Points for Mark Scheme |
|---|---|---|
| MCQ | "Which of the following is NOT a cause of hyperthermia?" | Differentiate fever (set point change) from hyperthermia (thermoregulation failure). Infection = fever, NOT hyperthermia. |
| MCQ | "PUO is defined as fever > X°C for > Y weeks..." | 38.3°C, 3 weeks, 1 week inpatient investigation |
| SAQ | "Define PUO and list 3 major categories of causes" | Definition verbatim + infections, autoimmune, malignancy (+ miscellaneous, no diagnosis) |
| SAQ | "A 60-year-old with 4 weeks of fever, negative cultures. What imaging?" | PET-CT |
| SAQ | "Differentiate fever from hyperthermia" | Table: set point, cytokines, diurnal variation, response to antipyretics, examples |
| SAQ | "List 3 infections commonly presenting as PUO" | Abdominal abscess, IE, TB |
| SAQ | "List 3 autoimmune diseases presenting as PUO" | SLE, vasculitis (GCA), Adult Still's disease |
| Minicase | Traveller returning with fever, relative bradycardia, rose spots | Typhoid fever (Faget's sign, Salmonella typhi) |
| Minicase | Post-chemo patient with ANC 0.1, fever 38.5°C | Neutropenic fever → blood cultures + empirical broad-spectrum Abx within 1 hour |
| MCQ | "Procalcitonin is most useful for distinguishing..." | Bacterial vs viral infection |
Common Traps
- Confusing fever thresholds at different sites: Oral 37.8°C ≠ Rectal 38°C ≠ Axillary 37.2°C. Know which site is being measured.
- PUO threshold vs fever threshold: PUO requires > 38.3°C, not just > 37.8°C.
- Drug fever as a diagnosis of exclusion: Don't diagnose drug fever without ruling out infection first. Look for temporal relationship, eosinophilia, rash.
- Hyperthermia treated with antipyretics: This is WRONG. Antipyretics lower the set point via COX inhibition; in hyperthermia the set point is normal — physical cooling is needed.
- Assuming PUO = exotic disease: Most PUOs are common diseases presenting atypically.
- Forgetting TB in the elderly: Cryptic miliary TB — non-specific symptoms, sputum AFB negative, TST negative. Consider empirical anti-TB therapy for PUO.
- Not ordering PET-CT: In PUO workup when CT is negative, PET-CT is the next step and the highest yield imaging modality.
High Yield Summary
Fever = core temperature above defined thresholds (oral ≥ 37.8°C, rectal ≥ 38°C) due to raised hypothalamic set point mediated by endogenous pyrogens (IL-1, TNF-α, IFN) → PGE2. Hyperpyrexia ( > 40°C) indicates serious pathology and risk of brain damage.
Fever ≠ Hyperthermia: Fever = set point raised (cytokine-mediated, responds to antipyretics). Hyperthermia = thermoregulation failure (heatstroke, NMS, serotonin syndrome, MH — requires physical cooling).
Fever patterns: Continuous (pyrogenic infections, dengue), Remittent (IE, typhoid, brucellosis), Intermittent (malaria, TB, Lyme).
Causes: Infections (most common), autoimmune (SLE, Still's, GCA), malignancy (lymphoma, RCC), tissue destruction, metabolic (gout), drugs.
Drug fever mechanisms: Hypersensitivity (most common), altered thermoregulation (anticholinergics, sympathomimetics, thyroid hormone), pharmacological extension, idiosyncratic (MH, NMS, serotonin syndrome).
PUO definition: Fever > 38.3°C on several occasions + > 3 weeks duration + no diagnosis after 1 week inpatient investigation. Big three causes: infections (abscess, IE, TB), autoimmune (SLE, vasculitis, Still's), malignancy (lymphoma). Increasing proportion: "no diagnosis" (good prognosis).
Workup: History (localising Sx, drugs, travel, animals, immunosuppression) → PE (comprehensive, repeated) → Labs (ESR, CRP, PCT, CBC, cultures, autoimmune, HIV) → Imaging (CT → PET-CT).
ESR: Increased by age, female sex, pregnancy, anaemia, renal disease. Decreased by RBC abnormalities, leukocytosis, hyperviscosity. CRP: More specific, faster kinetics. PCT: Most specific for bacterial infection.
PET-CT is the most useful imaging modality for PUO when initial workup is unrevealing.
Active Recall - Fever (GC 048)
[1] Lecture slides: GC 048. Fever.pdf (all pages) [2] Senior notes: Block A - Fever.pdf; Maksim Surgery Notes.pdf (post-op fever, 5 W's); Gen Clerk Anaes + Microbiology Summary.pdf (cryptic miliary TB); Block A - Fever after a blood transfusion_ transfusion and related problems.pdf [3] Past papers: 2019 Fourth Summative Mini Case.pdf (Case 1 — typhoid); 2021 Fourth Summative SAQ.pdf (Q12 — neutropenic fever); 2023 Fourth Summative Minicase.pdf (Case 3 — S. aureus spondylitis, septic shock); 2024 Fourth Summative SAQ.pdf (Q7 — septic arthritis; Q11 — sepsis management) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (neutropenic fever definition and management) [5] Paediatrics: The febrile infant (younger than 90 days of age)_ Definition of fever - UpToDate.pdf
GC047 Family History Of Anaemia
A documented record of anemia occurring in one or more blood relatives, suggesting a possible hereditary predisposition to conditions such as sickle cell disease, thalassemia, or other inherited anemias.
GC049 Fever After A Blood Transfusion
A febrile reaction occurring during or shortly after a blood transfusion, most commonly caused by recipient antibodies against donor leukocyte antigens or cytokines accumulated in stored blood products.