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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]

  1. Definition of fever
  2. Mechanisms of fever
  3. Causes of fever
  4. Definition of Pyrexia of Unknown Origin
  5. Differential diagnosis of PUO
  6. 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]

SiteNormal RangeWhy Different
Oral33.2–38.2°CAccessible but affected by recent drinks and mouth-breathing
Rectal34.4–37.8°CApproximates core temperature but is invasive and context-dependent
Tympanic35.4–37.8°CQuick, but technique, cerumen and device calibration affect accuracy
Axillary35.5–37.0°CNon-invasive but less reliable as a core-temperature surrogate

These are the wide observational ranges reproduced on the slide, not interchangeable universal reference intervals. Record the site and device, repeat an implausible value, and use the threshold specified by the relevant clinical pathway.

Normal temperature also depends on age, sex, time of measurement, activity level, etc. [1]

  • Diurnal variation: The historical 24-hour graph falls to about 36.2–36.4°C during sleep/early morning, rises after waking and peaks around 37.4–37.6°C in the late afternoon. The exact amplitude varies; the teaching point is that time of day changes the baseline.
  • 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 vasodilationCutaneous vasoconstriction
SweatingShivering (involuntary skeletal muscle contraction)
Behavioural (seeking shade, removing clothes)Behavioural (seeking warmth, adding clothes)
Decreased metabolic rateIncreased metabolic rate (brown fat thermogenesis in neonates)

The feedback diagram also includes voluntary responses. Heat exposure promotes loose clothing, cool drinks, reduced activity and seeking a cooler environment; cold exposure promotes warm clothing, food, activity and seeking heat. Autonomic responses work in parallel: sweating/vasodilation increase heat loss, while vasoconstriction and shivering conserve or generate heat.

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]

SiteFever Threshold
Oral≥ 37.8°C
Rectal≥ 38.0°C
Tympanic≥ 38.0°C
Axillary≥ 37.2°C

High Temperature: Interpret the Mechanism

Hyper-pyrexia is defined as core temperature > 40°C. [1]

  • Indicates a serious underlying condition

The slide also warns of permanent brain injury. Treat that as a mechanism- and duration-dependent risk, not an automatic consequence of this number. Published cut-offs for “hyperpyrexia” vary. A temperature around or above 40°C is an urgent clinical signal, but temperature alone does not establish mechanism. Unregulated hyperthermia—especially heatstroke with altered mental status—can rapidly cause coagulopathy and multiorgan/CNS injury and requires immediate active cooling [6].

Paediatric note (for integration)

In young infants, a documented temperature ≥38.0°C triggers an age-specific febrile-infant pathway; follow the local protocol for the accepted measurement site and device rather than converting between sites with a fixed offset [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:

  1. Trigger: Exogenous pyrogens (bacterial products like LPS/endotoxin, viral particles, fungal wall components) are detected by immune cells (monocytes, macrophages, neutrophils).
  2. 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)
  3. 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.
  4. Set-point elevation: PGE2 binds to EP3 receptors on thermoregulatory neurons in the preoptic area → raises the set point.
  5. Effector response: Body perceives current temperature as "too cold" → triggers shivering, vasoconstriction, behavioural warmth-seeking → temperature rises to the new set point.
  6. 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.

The mechanism figure links these steps visually: infection/LPS activates monocytes → IL-1, TNF-α and IL-6 enter the circulation → hypothalamic endothelial PGE₂ signals through EP3 → the thermostat commands heat conservation/production. This explains why a patient may feel cold and shiver while core temperature is rising, then sweat when the set point 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]

FeatureFeverHyperthermia
MechanismChange in hypothalamic set pointFailure in thermoregulation
MediatorsCytokine–PGE₂ signalling raises the set pointNot driven by a pyrogen-induced set-point rise; secondary inflammation may still occur
Diurnal variationMay remain recognisableNot a reliable discriminator in an acutely ill patient
Response to antipyreticsYes (NSAIDs/paracetamol lower set point)No (set point is normal; problem is excess heat production or inadequate dissipation)
Upper ceilingUsually self-limited (rarely > 41°C)Can exceed 41°C; no physiological brake
ExamplesInfections, autoimmune, malignancyHeatstroke, malignant neuroleptic syndrome, serotonin syndrome, thyroid storm

Critical Distinction

Fever = set point UP (regulated). Hyperthermia = heat production/absorption exceeds heat loss (unregulated). Heatstroke requires immediate active cooling; antipyretics do not correct its mechanism and may worsen hepatic, renal or coagulation injury [6]. Drug-induced syndromes need toxin-specific supportive and antidotal management as well as cooling.

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): Usually follows dopamine blockade/withdrawal of dopaminergic therapy; rigidity, altered consciousness, autonomic instability and elevated CK. Stop the trigger and obtain urgent critical-care/toxicology input; targeted drugs are case-dependent.
  • Serotonin toxicity: Serotonergic exposure plus clonus/hyperreflexia, agitation and autonomic features. Stop serotonergic drugs, provide sedation/supportive cooling, and seek toxicology advice for severe disease.
  • Thyroid storm: Decompensated thyrotoxicosis with CNS and cardiovascular/GI dysfunction; use a validated clinical framework and urgent endocrine/critical-care treatment rather than temperature alone.
  • 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]

PatternDescriptionCauses
ContinuousTemperature does not fluctuate > 1°C (remains elevated throughout)Pyrogenic infections, dengue fever, fungal infections
RemittentTemperature remains above normal but fluctuates > 1°CInfective endocarditis, brucellosis, typhoid fever
IntermittentElevation of temperature is present only for a certain period (returns to normal between spikes)Malaria, tuberculosis, Lyme disease, borreliosis, EBV

The four traces show the morphology: continuous curves stay above baseline with < 1°C fluctuation; remittent curves stay febrile but swing > 1°C; intermittent curves return to normal between peaks. These patterns are descriptive, not diagnostic. Antipyretics, antibiotics, measurement timing and host response often erase classic patterns, so use them only as supporting clues.

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 is classically associated with a stepladder rise and relative bradycardia, but neither is pathognomonic. In the 2019 minicase, travel from Bangladesh, high fever, relative bradycardia, rose spots and evolving bowel symptoms form the diagnostic cluster [3].

6. Causes of Fever — Systematic Classification

The lecture categorises causes of fever into 6 major groups [1]

CategoryConditionsWhy Fever Occurs
InfectionsVirus, bacteria, fungus, parasiteExogenous pyrogens (microbial products) → cytokine release → PGE2
Autoimmune diseasesSLE, Adult Still's disease, Giant cell arteritis, SarcoidosisChronic immune activation → persistent cytokine release
MalignanciesLymphoma, leukaemia, renal cell carcinomaTumour cells produce cytokines (IL-6, TNF-α) directly; tumour necrosis releases pyrogens
Tissue destructionMassive infarction, massive haemolysis, rhabdomyolysisNecrotic tissue releases intracellular contents → inflammatory response
Metabolic disordersGout, porphyriaCrystal deposition (gout: urate crystals) → inflammasome activation → IL-1β release
DrugsAntibiotics, anticonvulsantsMultiple 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).

The four-panel hypersensitivity diagram supplies the mechanism behind these labels [1]: type I is IgE/mast-cell degranulation; type II is antibody-mediated cellular injury through complement or ADCC; type III is immune-complex deposition with complement/neutrophils; and type IV is sensitised T-cell cytokine/cytotoxic injury. Drug fever can sit within a broader hypersensitivity syndrome, so actively look for rash, eosinophilia, cytopenia, lymphadenopathy and organ injury rather than treating fever as an isolated adverse effect.

  • 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” is a memory aid, not a validated day-by-day diagnostic rule. Atelectasis alone is not an established cause of postoperative fever, and infection, thrombosis, transfusion/drug reactions and tissue inflammation can occur outside mnemonic timelines. Use the operation, devices, symptoms, examination and trajectory to target testing [2].

8. Pyrexia of Unknown Origin (PUO / FUO)

This is the centrepiece of the lecture and a perennial exam favourite.

PUO is defined as:

  1. Fever > 38.3°C on several occasions
  2. Duration > 3 weeks
  3. 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: Reflected the diagnostic environment of 1961.

Historical Exam Definition vs Current Consensus

The three Petersdorf–Beeson criteria are the lecture/exam definition. Current 2024 Delphi consensus instead defines FUO in an immunocompetent patient as documented temperature ≥38.3°C on at least three occasions, illness lasting ≥3 weeks, and no explanation after completing a specified minimum diagnostic work-up; it no longer requires one week in hospital [7]. State which definition you are using.

CategoryDefinition
Classical PUOAs above (community-acquired, immunocompetent)
Nosocomial PUOHospitalised patient, fever developing ≥ 3 days after admission, no infection present on admission
Neutropenic PUOANC ≤ 500/µL + fever, no diagnosis after 3 days investigation
HIV-associated PUOHIV-positive patient, fever > 4 weeks (outpatient) or > 3 days (inpatient)

This expanded taxonomy remains useful for recognising context, but the current classical-FUO consensus deliberately focuses on immunocompetent patients. Nosocomial, neutropenic and HIV-associated fever need their own time-critical diagnostic and empirical-treatment pathways rather than being worked up as ordinary classical FUO [7].

The lecture shows evolving data from 1913–2005 demonstrating a shift in PUO causes [1]

CategoryKey ConditionsTrend Over Time
InfectionsAbdominal abscess, endocarditis, mycobacterial (TB)Decreasing proportion in developed countries (better diagnostics)
MalignanciesLymphoma, solid organ tumoursDecreasing (earlier cancer detection with CT/PET)
Connective tissue diseasesSLE, vasculitis, Adult Still's diseaseIncreasing relative proportion
MiscellaneousDrug fever, factitious fever, DVT/PE, thyroiditis, granulomatous conditionsStable
No diagnosisNo cause after structured work-up; many stable immunocompetent cohorts have favourable outcomes, but follow-up is still requiredIncreasing (up to 50% in some series)

Reading the stacked chart: the proportions change dramatically between cohorts rather than following one smooth temporal trend. Infection occupies roughly 80% in one 1989–93 series but only about one fifth in the 2003–05 series, where “no diagnosis” is about half. This heterogeneity reflects geography, referral selection, immune status and available diagnostics; never transfer one bar's percentages directly to an individual patient.

The accompanying pie charts are also historical cohort composition, not universal prevalence: among infectious diagnoses, endocarditis is the largest sector, followed by mycobacterial disease and abdominal abscess; among malignancies, lymphoma is about two thirds and solid tumours about one third [1]. Their practical message is where to look—endovascular infection, deep abscess, TB and tissue suitable for lymphoma biopsy.

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 or miliary TB in older/immunocompromised patients. Negative sputum or immune-based testing does not exclude extrapulmonary disease; pursue microbiological and histological confirmation from the safest highest-yield site. Empirical treatment without evidence is a specialist risk–benefit decision, not a routine FUO step.

  • SLE: Young women; malar rash, arthritis, serositis, cytopenias. Check ANA, anti-dsDNA, complement levels.
  • Vasculitis: Giant cell arteritis (older patient, new headache, jaw claudication or visual symptoms, inflammatory markers). When sight is threatened, urgent treatment must not wait; ultrasound/vascular imaging and/or temporal artery biopsy support diagnosis according to local expertise.
  • 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]

The four-box figure is best read as an iterative loop, not four independent shopping lists: history creates potential diagnostic clues; repeated examination refines them; targeted laboratory tests and imaging then confirm, redirect or identify a safe biopsy site. Revisit all four whenever the trajectory changes.

  • 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: exact fever documentation and timeline; sick contacts; food/water and unpasteurised dairy; vector and freshwater/soil exposure; occupation/hobbies; sexual and blood-borne risks; implanted material and recent dental/procedural/surgical care; transfusion; family/ethnic history of periodic fever syndromes; and every prescribed, over-the-counter, traditional and recreational drug with start/stop dates.

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

Reading the diagrams: ESR is the distance erythrocytes fall through a vertical anticoagulated blood column in one hour. Fibrinogen, other acute-phase proteins and immunoglobulins reduce repulsion between RBCs, allowing coin-stack rouleaux to form and settle faster; albumin opposes rouleaux. Anaemia accelerates settling by changing cell concentration, whereas abnormal cell shape, polycythaemia/hyperviscosity and extreme leukocytosis can slow it. Thus ESR is an indirect physical phenomenon, not a concentration of one inflammatory protein.

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.

  • Infection/inflammation signals—especially IL-6 with IL-1β—induce hepatocyte CRP transcription and secretion.
  • The figure shows pentameric plasma CRP binding microbial and damaged-cell ligands, interacting with C1q/complement and Fc receptors to support opsonisation and clearance.
  • CRP usually changes faster than ESR and is less distorted by anaemia or RBC morphology, which makes serial trends useful.
  • It remains non-specific: bacterial and non-bacterial infection, sterile tissue injury, inflammatory disease and malignancy can all produce high values. No single CRP threshold proves or excludes bacterial infection.
  • Under normal endocrine control, thyroid C cells process procalcitonin toward calcitonin. The paired tissue-expression figures show the contrast in sepsis: bacterial LPS, IL-1β and TNF-α can switch on widespread extra-thyroid PCT production (liver, kidney, lung, fat and other tissues), whereas interferon-γ can suppress this response in many viral infections.
  • The kinetics plot shows TNF-α/IL-6 rising first, PCT rising within hours and peaking around 12–24 hours, and CRP peaking later. With effective therapy PCT often falls; persistent/rising curves may signal uncontrolled infection or source failure.
  • This biology is probabilistic, not binary. Early/localised bacterial infection can have low PCT, while renal dysfunction, major trauma/surgery, shock and some malignancies can raise it without bacterial infection.

Current safety point: do not use a universal PCT cut-off to decide that a patient has “bacterial sepsis,” and do not delay indicated antimicrobials because PCT is low. The 2026 Surviving Sepsis Campaign prefers clinical evaluation alone over adding PCT to decide whether to start antibiotics; after source control, serial PCT plus clinical evaluation may help decide when to stop if duration remains unclear [8].

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: Faster response and fewer haematological confounders than ESR, but still non-specific; trend in clinical context.
  • PCT: Can modify the probability of systemic bacterial infection and support selected stewardship protocols, but neither rules infection in/out nor replaces cultures, source assessment or clinical judgement.

  • CBC with differential: Neutrophilia (bacterial), lymphocytosis (viral, TB), eosinophilia (parasites, drugs, lymphoma), pancytopenia (marrow infiltration, SLE)
  • Blood cultures: Obtain appropriate sets from separate venepunctures before antibiotics where feasible, but never delay time-critical treatment of sepsis or febrile neutropenia.
  • 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)

  • Cross-sectional CT is commonly included in the minimum FUO evaluation or targeted to potential diagnostic clues.
  • CT chest/abdomen/pelvis can identify abscesses, lymphadenopathy, solid-organ masses and splenomegaly, while also providing anatomy for biopsy or drainage planning.

  • Superior soft tissue resolution
  • Particularly useful for CNS infection/inflammation and spinal infection (spondylodiscitis—tested in the 2023 minicase [3]) or another anatomically localised question. Suspected endocarditis is evaluated primarily with echocardiography, with cardiac CT/PET/MRI used selectively for complications or prosthetic material.

  • 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 useful after a standard evaluation remains unrevealing or when systemic inflammatory disease is suspected [9].
  • 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
  • Can guide biopsy (e.g., lighting up lymph node → targeted biopsy)

Reading the PET-CT slide: CT supplies anatomy, PET supplies glucose-uptake intensity, and fused axial images co-localise the two; the maximum-intensity projection gives a one-view whole-body map. Physiological uptake/excretion—especially brain, variable myocardium, kidneys and bladder—must be distinguished from pathological foci. FDG uptake is sensitive to inflammatory activity but not disease-specific.

The evidence table is historical (small studies from 2000–2010): across 548 patients, PET was reported “helpful” in a mean 47%, but individual studies ranged from 16% to 89% and used different scanners/definitions. Do not quote the mean as a universal diagnostic yield. Current EANM consensus emphasises patient selection after adequate basic work-up, expert interpretation and using PET to direct more specific tests or biopsy [9].

PET-CT in PUO — Exam Favourite

For the lecture's “persistent FUO with unrevealing standard tests” scenario, FDG PET-CT is a high-yield next whole-body investigation. In practice it is not automatic after every negative CT: choose it when the result can localise occult inflammation/malignancy, guide tissue sampling or support monitored observation after multidisciplinary review [9].

10. Integration: Fever in Special Contexts

  • Definition: ANC ≤500/µL (or expected to fall to this level) with a single oral temperature ≥38.3°C or ≥38.0°C sustained for at least 1 hour.
  • Medical emergency: triage/risk stratify, collect appropriate cultures promptly and give protocol-based empirical antipseudomonal antibacterial therapy within 1 hour of triage; cultures must not create a treatment delay [10]. Agent and inpatient/outpatient pathway depend on stability, allergy, organ function, local resistance and anticipated neutropenia duration.
  • Past paper 2021 SAQ Q12 directly tests this [3]

  • First action: stop the transfusion, keep IV access with appropriate fluid, check patient/unit identity and notify the transfusion service. Assess for acute haemolysis and bacterial contamination before labelling the event benign.
  • Febrile non-haemolytic transfusion reaction: fever/chills after other dangerous causes have been excluded; often related to recipient cytokine/antileukocyte responses.
  • 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]

  • The “5 W's” can prompt categories but should not assign causes by postoperative day. Review the operation, aspiration/lung findings, lines/catheters, urine symptoms, wound, abdominal source, transfusion/drugs and VTE risk; test according to clinical clues.

No question isolates the whole PUO algorithm, but the principles recur in integrated cases: travel-associated typhoid (2019 minicase), febrile neutropenia (2021 SAQ), S. aureus spondylitis/sepsis (2023 minicase), and septic arthritis/sepsis management (2024 SAQ) [3].

Common Traps

  1. Confusing fever thresholds at different sites: Oral 37.8°C ≠ Rectal 38°C ≠ Axillary 37.2°C. Know which site is being measured.
  2. PUO threshold vs ordinary fever threshold: the historical slide uses > 38.3°C; current consensus uses documented ≥38.3°C on at least three occasions plus duration and minimum-work-up criteria.
  3. Drug fever as a diagnosis of exclusion: Don't diagnose drug fever without ruling out infection first. Look for temporal relationship, eosinophilia, rash.
  4. 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.
  5. Assuming PUO = exotic disease: Most PUOs are common diseases presenting atypically.
  6. Treating a negative sputum/TB immune test as exclusion of extrapulmonary TB: pursue microbiology/histology from an appropriate site; empirical therapy is specialist-led, not an automatic FUO trial.
  7. Ordering PET-CT as a reflex after any negative CT: first verify the standard FUO work-up and potential diagnostic clues; PET-CT is most useful when it can localise systemic disease or direct biopsy.

High Yield Summary

  1. Fever

    • The lecture's site-specific thresholds (for example oral ≥37.8°C and rectal ≥38°C) are operational cut-offs; document site/device. Fever reflects a raised hypothalamic set point mediated by cytokines → PGE₂.
    • The lecture calls core temperature > 40°C “hyperpyrexia”; treat it urgently, but distinguish regulated fever from unregulated hyperthermia because mechanism, injury risk and treatment differ.

  2. Fever ≠ Hyperthermia

    • Fever = set point raised (cytokine-mediated, responds to antipyretics). Hyperthermia = thermoregulation failure (heatstroke, NMS, serotonin syndrome, MH — requires physical cooling).

  3. Fever patterns

    • Continuous, remittent and intermittent curves describe temperature behaviour but are non-specific and should not substitute for exposure/microbiology data.

  4. Causes

    • Infections (most common), autoimmune (SLE, Still's, GCA), malignancy (lymphoma, RCC), tissue destruction, metabolic (gout), drugs.

  5. Drug fever

    • mechanisms: Hypersensitivity (most common), altered thermoregulation (anticholinergics, sympathomimetics, thyroid hormone), pharmacological extension, idiosyncratic (MH, NMS, serotonin syndrome).

  6. PUO definition

    • Historical slide definition: fever > 38.3°C on several occasions + > 3 weeks + no diagnosis after one inpatient week. Current consensus: ≥38.3°C on ≥3 occasions for ≥3 weeks in an immunocompetent patient, unexplained after a specified minimum work-up.
    • Big three causes: infections (abscess, IE, TB), autoimmune (SLE, vasculitis, Still's), malignancy (lymphoma).
    • “No diagnosis” is common in modern cohorts; stable patients may do well but still require structured follow-up.

  7. Workup

    • Iterate history/exposure and repeated examination with the minimum laboratory/imaging work-up; use clues to target microbiology, imaging and the safest high-yield biopsy. Consider FDG PET-CT when systemic disease remains occult.

  8. ESR

    • Increased by age, female sex, pregnancy, anaemia and renal disease; decreased by some RBC abnormalities, extreme leukocytosis and hyperviscosity. CRP changes faster but is still non-specific. PCT modifies bacterial probability but must not determine antibiotic initiation alone.

  9. PET-CT

    • combines whole-body metabolic mapping with anatomical localisation and can direct biopsy after a standard FUO work-up; FDG uptake is not disease-specific.

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 [6] Wilderness Medical Society. Clinical Practice Guidelines for the Prevention and Treatment of Heat Illness: 2024 Update [7] International Fever and Inflammation of Unknown Origin Research Working Group. Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel [8] Society of Critical Care Medicine. Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock 2026 [9] European Association of Nuclear Medicine. Consensus document on the use of 18F-FDG PET/CT in fever and inflammation of unknown origin [10] ASCO/IDSA. Clinical Practice Guideline Update for Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy

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.

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