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Approach to Fever

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1. Definition

• Temperature >99°F (37.2°C) at 6 AM, OR
• Temperature >100°F (37.8°C) at any time of day

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2. Pathobiology of Fever

Mechanism of Fever Generation

Patients who fail to mount a fever during severe bacterial infection have higher morbidity and mortality, suggesting fever may inhibit pathogen replication or enhance neutrophil recruitment.

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3. Clinical Manifestations

Vital Sign Changes with Fever

• Tachycardia: ~2-5 beats/min per 1°F rise in temperature
• Peripheral vasodilation: contributes to tachycardia, may blunt BP rise
• Relative or absolute hypotension: signals possible septic shock (poor prognosis)

Temperature-Pulse Dissociation (Faget's Sign)

• Typhoid fever
• Leptospirosis
• Rickettsiosis
• Dengue
• Legionellosis
• Babesiosis

Localizing Symptoms by System

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4. History - Key Elements

• Onset and duration - acute vs. subacute vs. chronic
• Pattern - continuous, intermittent (quotidian, tertian, quartan), remittent, hectic/septic
• Associated symptoms - localizing symptoms by organ system
• Exposures - sick contacts, animal exposures, insect bites, injection drug use, sexual history
• Travel history - geographic-specific infections (malaria, typhoid, dengue, amoeba, etc.)
• Medications - drug fever, immunosuppressants
• Vaccination status - reduces risk of many infections, though immunity may wane
• Comorbidities - diabetes, HIV, malignancy, organ transplant, splenectomy
• Occupation / hobbies

Epidemiological Transmission Routes

• Direct contact (hands, fomites)
• Common source (food, water)
• Aerosol/respiratory droplets (viral respiratory infections)
• Vector-borne (mosquitoes - malaria, dengue; ticks - Lyme, RMSF, ehrlichiosis)
• Zoonoses
• Skin breach / injection drug use

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5. Physical Examination

• General: toxicity, dehydration, diaphoresis
• Skin: rash (character, distribution - see below), petechiae, jaundice, track marks
• Eyes: conjunctival hemorrhage (endocarditis), icterus
• Oropharynx: exudates, ulcers, Koplik spots
• Lymph nodes: lymphadenopathy (location, size, tenderness)
• Heart: new murmur (endocarditis)
• Lungs: consolidation, effusion
• Abdomen: hepatosplenomegaly, tenderness, guarding
• Joints: swelling, warmth, restricted motion
• Neurological: meningismus, focal signs, altered sensorium
• Genitalia/Rectum: lesions, fluctuance (abscess)

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6. Fever with Rash - Special Approach

• Rocky Mountain Spotted Fever (Rickettsia rickettsii)
• Syphilis (Treponema pallidum)
• Hand-foot-and-mouth disease (Coxsackie)
• Endocarditis (Osler nodes, Janeway lesions)
• Toxic shock syndrome

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7. Fever with Musculoskeletal Complaints

• Localized tenderness/swelling/erythema → septic arthritis, osteomyelitis, spinal epidural abscess
• Polyarthritis → disseminated gonococcal infection, chikungunya, dengue, parvovirus B19, Hepatitis B/C, Lyme disease
• Vertebral osteomyelitis → almost always begins as discitis with symmetrical involvement of adjacent vertebrae
• Myositis → clostridial, streptococcal, or mixed aerobic-anaerobic infections; deep muscle myositis (psoas, gluteus) usually S. aureus

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8. Diagnostic Approach

Initial Workup

• CBC with differential
• CRP, ESR, procalcitonin
• Blood cultures (2 sets before antibiotics)
• Urine analysis + culture
• LFTs, renal function, electrolytes
• Chest X-ray (if respiratory symptoms)

• Throat swab, rapid strep test
• Lumbar puncture (if meningitis suspected)
• Joint aspiration (septic arthritis)
• Wound swab
• Stool culture / C. difficile PCR
• Serology for specific infections (EBV, CMV, HIV, dengue, malaria smear, leptospira, etc.)
• Imaging (CT, US) for deep-seated infection

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9. Fever of Unknown Origin (FUO)

• Fever >38.3°C (101°F) on multiple occasions
• Duration >3 weeks
• No diagnosis after 1 week of inpatient investigation (or after 3 outpatient visits)

Major Categories of FUO

FUO Workup Strategy

1. Detailed history re-review (medications, travel, family history, occupational exposures)
2. Repeat physical examination - look for subtle nodes, rashes, organomegaly
3. Lab: ANA, ANCA, RF, ferritin (very high in Still's), LDH, SPEP, HIV, TB IGRA/TST, blood cultures (multiple)
4. Imaging: CT chest/abdomen/pelvis, PET-CT (high sensitivity for occult malignancy, infection, and inflammation), echocardiography
5. Bone marrow biopsy (if hematologic malignancy or disseminated infection suspected)
6. Liver biopsy (if granulomatous disease suspected)
7. Tissue biopsy of any accessible lesion

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10. Fever in Special Populations

Neutropenic Fever (Oncology)

• Defined as temperature >38.3°C (101°F) single reading OR >38°C (100.4°F) sustained for 1 hour in a patient with ANC <500/μL
• Medical emergency - start broad-spectrum antibiotics empirically within 1 hour
• Common organisms: gram-negative rods (P. aeruginosa, E. coli, Klebsiella), Staphylococci, Candida
• Risk stratification with MASCC score guides inpatient vs. outpatient management

Immunocompromised Host (General)

• Signs of inflammation (fever, erythema, pain) may be blunted or absent
• Broader differential including opportunistic pathogens
• Type of immune defect predicts likely pathogens:
  • TNF-inhibitors → Tuberculosis, Histoplasma
  • Splenectomy/asplenia → Encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis)
  • T-cell defects → PCP, CMV, Toxoplasma, Cryptococcus, NTM
  • B-cell defects → Encapsulated bacteria, Giardia, enteroviruses

Returning Traveler with Fever

• Fever within 3 months of travel to endemic area - malaria must be excluded
• Key diagnoses by geography: malaria (Sub-Saharan Africa), dengue (Southeast Asia, Caribbean), typhoid, hepatitis A, leptospirosis, rickettsial disease, amoebic liver abscess
• Thick and thin blood films + RDT for malaria are urgent

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11. Treatment Principles

Antipyretics

• Acetaminophen (paracetamol): 500-1000 mg q4-6h (max 4g/day)
• Ibuprofen / NSAIDs: effective antipyretics, avoid in dehydrated patients, renal impairment, GI disease
• Aspirin: avoid in children (Reye syndrome risk)
• Fever is generally beneficial - antipyretics should be used mainly for patient comfort or when fever is harmful (e.g., seizure-prone children, cardiac patients, pregnant women)

Antimicrobials

• Empiric antibiotics warranted when: sepsis, neutropenic fever, meningitis, immunocompromised patient, life-threatening presentation
• Otherwise, defer antibiotics until a pathogen is identified to avoid:
  • Masking the diagnosis
  • Promoting antimicrobial resistance
  • Adverse drug effects
• De-escalate based on culture results and clinical response
• Duration: shorter courses are generally better and reduce resistance selection

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12. Summary: Algorithmic Framework

FEVER DETECTED
     │
     ├─ Hemodynamic instability? → Sepsis protocol, urgent cultures, empiric antibiotics
     │
     ├─ Neutropenia / Immunosuppression? → Broad empiric antibiotics, expanded differential
     │
     ├─ Localizing symptoms/signs?
     │     └─ YES → Targeted workup and directed therapy
     │
     ├─ Fever + Rash? → Classify rash; consider life-threatening causes first (meningococcemia, RMSF, SSSS)
     │
     ├─ Travel history? → Malaria smear (urgent!), dengue, typhoid, etc.
     │
     ├─ Duration >3 weeks, no diagnosis? → FUO workup
     │
     └─ Self-limited, low-risk, no localizing signs → Supportive care, watchful waiting

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Approach to Fever

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1. Definition and Normal Temperature

• Normal mean oral temperature: ~36.5°C (98°F) - significantly lower than the classical 98.6°F (37°C) figure, which was derived from 19th-century axillary measurements
• Temperature varies by site: rectal > oral > axillary; tympanic membrane (unadjusted mode) reads ~0.8°C below rectal
• Circadian variation: nadir in early morning (6 AM), zenith in late afternoon (4-6 PM)
• In menstruating women: temperature rises ~0.6°C after ovulation and stays elevated until menses

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2. Fever vs. Hyperthermia - Critical Distinction

This distinction is clinically vital - hyperthermia does not respond to NSAIDs or acetaminophen and requires physical cooling.

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3. Pathogenesis of Fever

Step 1 - Exogenous Pyrogens

Step 2 - Pyrogenic Cytokines (Endogenous Pyrogens)

Inflammatory processes WITHOUT infection (pericarditis, trauma, stroke, vaccination) also induce IL-1, TNF, and IL-6 → fever.

Step 3 - Hypothalamic Set-Point Reset

• Pyrogenic cytokines interact with endothelium of circumventricular vascular organs (organum vasculosum of lamina terminalis - OVLT) around the hypothalamus
• This raises prostaglandin E2 (PGE2) levels in hypothalamic tissue and the third ventricle
• PGE2 acts on hypothalamic thermoregulatory neurons → raises set point

Why NSAIDs and Aspirin Work

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4. Disease Categories That Present with Fever

1. Infectious diseases
2. Autoimmune and non-infectious inflammatory disorders
3. Cancer (malignancy-related fever)
4. Medication-related (drug fever, vaccines)
5. Endocrine disorders (e.g., thyroid storm, hyperthyroidism)
6. Intrinsic hypothalamic malfunction

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5. History and Physical Examination

History

• Chronology of events preceding fever
• Exposure to symptomatic individuals, vectors, contaminated food/water
• Travel history (geographic exposures)
• Medications - note: patients on glucocorticoids, anti-IL-1, anti-IL-6, anti-TNF therapy may have active severe infection WITHOUT fever due to blunted febrile response
• Vaccination status
• Comorbidities: renal/hepatic failure (blunted fever), immunosuppression, cardiac prostheses
• Occupation, hobbies, animal exposure, sexual history

Special alert (Harrison's): Newborns, elderly patients, patients with chronic hepatic or renal failure, and those taking glucocorticoids or anticytokine therapy may have active disease WITHOUT fever.

Physical Examination

• Skin and rash (morphology, distribution, progression)
• Lymphadenopathy
• Oropharynx
• Cardiac auscultation (new murmur → endocarditis)
• Abdomen (hepatosplenomegaly, tenderness)
• Joints (swelling, erythema, restricted motion)
• CNS (meningismus, focal signs)

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6. Laboratory Workup

• CBC with differential - manual or instrument-based; look for neutrophilia with band forms, toxic granulations, Döhle bodies (bacterial infection); neutropenia (some viral infections)
• CRP and ESR - most valuable in low-grade or occult fever; CRP stays elevated (unlike IL-6 which varies)
• IL-6 measurement - may be useful as it drives CRP
• Circulating cytokines (IL-1, TNF) - not helpful clinically; often below detection limit or don't correlate with fever
• Blood cultures, urine cultures - targeted to clinical picture
• Directed serology and molecular testing based on history and examination

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7. Fever and Rash

Approach to History

• Immune status
• Medications in the previous month
• Travel history
• Immunization status
• Animal and arthropod exposures
• Dietary exposures
• Cardiac abnormalities / prosthetic material
• Sexual exposures
• Site of rash onset + direction and rate of spread

Classification of Rash Lesions

Key Differential by Rash Type (Summary)

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8. Fever of Unknown Origin (FUO)

Updated Definition (Harrison's 22E, 2025)

1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Illness duration of at least 3 weeks
3. No known immunocompromised state (immunocompromised patients require a separate, more aggressive protocol)

The original Petersdorf-Beeson (1961) definition also required "1 week of inpatient evaluation without diagnosis" - current practice uses outpatient workup criteria as well.

Etiology - Data from Large Studies (Harrison's Table 22-1, 2005-2023)

• Tuberculosis (most common globally)
• Infective endocarditis
• Intra-abdominal / pelvic abscesses
• Osteomyelitis / spondylodiscitis
• Brucellosis, Q fever (Coxiella burnetii), bartonellosis
• HIV, EBV, CMV
• Lyme disease, leptospirosis, legionellosis

• Adult-onset Still's disease
• SLE, vasculitis (giant cell arteritis, PAN, ANCA)
• Rheumatoid arthritis (systemic)
• IBD, sarcoidosis

• Lymphoma (esp. Hodgkin's), leukemia
• Renal cell carcinoma, hepatocellular carcinoma
• Atrial myxoma

• Drug fever - virtually all drugs can cause it, even after long-term use; key culprits: allopurinol, carbamazepine, lamotrigine, phenytoin, sulfasalazine, vancomycin, β-lactam antibiotics, isoniazid, furosemide. Drug-induced fever may come with eosinophilia, lymphadenopathy (DRESS/DIHS)
• Factitious fever - patient manipulates thermometer; confirmed by simultaneous multi-site measurement
• Benign/exercise-induced hyperthermia - no CRP/ESR elevation, possibly post-infectious (post-EBV, Q-fever, COVID-19 long fever)
• Thyroiditis, hyperthyroidism
• Autoinflammatory diseases (newly recognized since the 1960s)

FUO Workup Strategy (Harrison's)

• Re-review history (medications, travel, occupational exposures, family history)
• Serial physical exams - watch for new lymph nodes, rashes, organomegaly

• ANA, ANCA, RF, complement, ferritin (very high >10,000 ng/mL in adult Still's disease)
• Serum protein electrophoresis (SPEP), LDH
• Blood cultures (3 sets, prolonged incubation for HACEK/Brucella)
• HIV, EBV, CMV, Hepatitis B/C serology
• TB - IGRA / TST + sputum AFB
• Echocardiography (transoesophageal if endocarditis suspected)

• CT chest/abdomen/pelvis - detect abscesses, masses, lymphadenopathy
• 18F-FDG-PET/CT - high sensitivity for occult malignancy, large-vessel vasculitis, infection. A normal PET/CT is associated with higher rates of spontaneous fever resolution
• MRI - osteomyelitis, spondylodiscitis, brain/spinal lesions

• Bone marrow biopsy (granuloma, haematological malignancy, disseminated infection)
• Liver biopsy (granulomatous hepatitis)
• Biopsy of accessible lesions (lymph node, skin, mass)
• Laparoscopy / laparotomy in selected cases

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9. Neutropenic Fever

Definition

• Single oral temperature ≥38.3°C, OR
• Temperature ≥38.0°C sustained over 1 hour
• PLUS ANC <500 cells/μL (or expected to fall to <500 cells/μL within 48 hours)

Key Principles

• Localizing signs and symptoms may be subtle or absent during neutropenia
• Infections progress rapidly
• Empirical broad-spectrum antibiotics must be started early whenever infection is suspected - do not wait for cultures
• Infection is documented in only ~40% of NF episodes by standard methods; newer plasma cell-free DNA PCR identifies a bacterial etiology in most cases
• Most organisms are from the patient's own microbiome (skin, bowel flora disrupted by chemotherapy)

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10. Fever in the ICU

2024 SCCM/IDSA Joint Guidelines (Replaces 2008 Guidelines)

• Scope: Evaluation of new-onset fever in adult ICU patients without severe immunocompromise
• Methodology: GRADE-based; issued 1 strong recommendation, 12 weak recommendations, 9 best practice statements; identified 4 areas where evidence was insufficient to recommend

1. Structured diagnostic approach before empiric antimicrobials
2. Integration of rapid molecular diagnostics and point-of-care ultrasound
3. Renewed emphasis on antimicrobial stewardship - avoid reflexive broad-spectrum antibiotics for all ICU fevers
4. Non-infectious causes of fever in the ICU (drug fever, transfusion reaction, DVT/PE, SIRS, adrenal insufficiency, acalculous cholecystitis) must be actively considered before committing to antibiotics

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11. Treatment of Fever

When to Treat

• Patient comfort (headache, myalgias, arthralgias)
• Patients with impaired cardiac, pulmonary, or CNS function (fever increases O2 demand by 13% per 1°C above 37°C)
• Children with history of febrile or non-febrile seizures - treat aggressively
• Pregnancy (especially high fever in first trimester)
• Hyperpyrexia (>41.5°C) - mandatory cooling

Antipyretics

Physical Cooling

• Cooling blankets may be used for hyperpyrexia
• Must be combined with antipyretics - without them, the hypothalamic set point remains elevated and the patient shivers (counterproductive)
• Especially important in hyperpyrexia with CNS disease or trauma - mitigates detrimental effects of high temperature on the brain

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12. Special Considerations

Fever in Patients on Anticytokine Therapy (Harrison's)

• Anti-TNF (infliximab, adalimumab, etanercept), anti-IL-1 (anakinra), anti-IL-6 (tocilizumab), anti-IL-17, anti-IL-12/23 therapy - all blunt the febrile response
• Latent TB can disseminate on anti-TNF therapy
• Anti-IL-17 in psoriasis increases risk of systemic candidiasis
• Despite blunted fever, fever is still among the presenting signs in nearly all reported infections in these patients - never be reassured by a normal temperature alone

Temperature Measurement Caveats

• Use the same site consistently to monitor a febrile illness
• At-risk groups who may have NO fever despite active infection: newborns, elderly, chronic hepatic/renal failure, patients on glucocorticoids or anticytokine therapy

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Summary Algorithm

ELEVATED TEMPERATURE
        │
        ├─ Distinguish FEVER vs. HYPERTHERMIA
        │     Hyperthermia → physical cooling ± specific antidotes (no antipyretics alone)
        │
        ├─ Blunted febrile response? (elderly, renal/hepatic failure, steroids, anticytokine Rx)
        │     → Treat as potential serious infection even without high fever
        │
        ├─ HISTORY: exposures, travel, medications, vaccinations, sexual hx, animal contact
        │
        ├─ PHYSICAL EXAM: full exam with focus on rash, nodes, heart, abdomen, joints, CNS
        │
        ├─ LOCALIZED source found? → Targeted workup + directed therapy
        │
        ├─ FEVER + RASH? → Classify rash; rule out meningococcemia, RMSF, TSS first
        │
        ├─ NEUTROPENIC? → Empiric broad-spectrum antibiotics urgently (ANC <500)
        │
        ├─ ICU patient? → Apply 2024 SCCM/IDSA structured evaluation framework;
        │                  consider non-infectious causes; antimicrobial stewardship
        │
        ├─ Travel history? → Malaria films + RDT urgently; dengue, typhoid, hepatitis
        │
        └─ Duration >3 weeks, no diagnosis → FUO workup
              CBC, CRP, ESR, blood cultures, ANA/ANCA, RF, ferritin, LDH, SPEP
              HIV, TB IGRA, EBV/CMV serology
              Echocardiography
              CT chest/abdomen/pelvis → 18F-FDG-PET/CT → Bone marrow/liver biopsy

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• Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw-Hill) - Chapter 20 (Fever), Chapter 21 (Fever and Rash), Chapter 22 (FUO), Chapter 79 (Neutropenic Fever)
• 2024 SCCM/IDSA Guidelines - New Fever in ICU Adults (replaces 2008 guidelines; GRADE-based; 1 strong + 12 weak recommendations + 9 best practice statements)

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APPROACH TO FEVER

Harrison's Principles of Internal Medicine, 22nd Edition (2025) + 2024 SCCM/IDSA Guidelines

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SECTION 1: NORMAL BODY TEMPERATURE AND THERMOREGULATION

Thermoregulatory Physiology

1. Signals from peripheral nerves carrying warmth/cold receptor data from the skin
2. Signals from the temperature of blood bathing the hypothalamic region

What is "Normal"?

• Mean oral temperature: 36.6°C (95% CI: 35.7–37.3°C)
• Fever threshold: >37.7°C (>99.9°F) = 99th percentile for healthy adults
• This replaces the classical 98.6°F/37.0°C which came from 19th-century axillary data

Factors That Modify Baseline Temperature

Clinical pearl (Harrison's 22E): An increase in baseline temperature of just 0.15°C (1 standard deviation) translates into a 0.52% absolute increase in 1-year mortality after controlling for all confounders.

Temperature Measurement by Site

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SECTION 2: DEFINITIONS

Fever

Hyperpyrexia

Hypothalamic Fever

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SECTION 3: FEVER vs. HYPERTHERMIA - A CRITICAL DISTINCTION

Causes of Hyperthermia (NOT Fever)

• Heat stroke (classic or exertional)
• Neuroleptic malignant syndrome (NMS) - dopamine blockade by antipsychotics
• Malignant hyperthermia - inhaled anesthetics + succinylcholine in susceptible individuals (RYR1/CACNA1A mutation)
• Serotonin syndrome - excess serotonergic activity
• Thyroid storm
• Pheochromocytoma crisis
• Drug-induced (cocaine, amphetamines, MDMA)

Key point (Harrison's): Hyperthermia is a medical emergency requiring physical cooling (ice water immersion, cooling blankets without antipyretics alone) and specific antidotes (dantrolene for MH/NMS, cyproheptadine for serotonin syndrome).

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SECTION 4: PATHOGENESIS OF FEVER - DETAILED MOLECULAR MECHANISM

Step 1: Exogenous Pyrogens

• Definition: Substances derived from outside the patient that cause fever
• Classic example: Bacterial lipopolysaccharide (LPS/endotoxin) from gram-negative outer membrane
  • Pyrogenic dose in IV volunteers: 2-3 ng/kg produces fever, leukocytosis, acute-phase proteins, malaise
• Gram-positive toxins: Less pyrogenic than endotoxin but produce toxins acting as superantigens
  • S. aureus: TSST-1, staphylococcal enterotoxins
  • Streptococcus: pyrogenic exotoxins
  • Pyrogenic at 1-10 μg/kg in animal studies

Step 2: Pyrogenic Cytokines (Endogenous Pyrogens)

Each pyrogenic cytokine is encoded by a separate gene. All have been shown to cause fever in both laboratory animals and humans.

Non-infectious triggers for pyrogenic cytokines: Pericarditis, trauma, stroke, routine immunizations - individually or together, these induce IL-1, TNF, and/or IL-6 → fever without any infection.

Step 3: The Hypothalamic Cascade

• Networks of enlarged capillaries surrounding hypothalamic regulatory centers
• Concentrations of PGE2 are highest here during fever
• Pyrogenic cytokines do NOT cross the blood-brain barrier directly - they interact with the endothelium of OVLT capillaries

Exogenous pyrogen (LPS) + Pattern Recognition Receptors (TLRs on macrophages)
    ↓
Synthesis of pyrogenic cytokines (IL-1, IL-6, TNF, IFN-γ)
    ↓
Cytokines interact with OVLT endothelium
    ↓
Activation of COX-2 (cyclooxygenase-2) in endothelial and glial cells
    ↓
Arachidonic acid → PGE2 synthesis
    ↓
PGE2 diffuses into hypothalamic preoptic area
    ↓
Acts on EP3 receptors on thermosensory neurons
    ↓
Raises hypothalamic set point (e.g., 37°C → 39°C)

• Vasomotor neurons activated → peripheral vasoconstriction
• Patient feels cold (hands, feet cold first)
• Shivering begins (muscle heat production)
• Nonshivering thermogenesis from liver also contributes
• Behavioral adjustments (adding clothing, curling up)
• Core temperature rises 1-2°C until it matches new set point → fever plateau

• Pyrogen concentration falls, OR antipyretic administered
• Set point resets downward
• Vasodilation + sweating dissipates heat
• Patient experiences diaphoresis and warmth ("fever breaking")

How Antipyretics Work

Chronic high-dose aspirin or NSAID therapy does not reduce normal core body temperature, confirming that PGE2 plays no role in normal thermoregulation - it is only relevant to the febrile state.

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SECTION 5: DISEASE CATEGORIES PRESENTING WITH FEVER

1. Infectious diseases (bacteria, viruses, fungi, parasites, prions)
2. Autoimmune and non-infectious inflammatory disorders (SLE, RA, vasculitis, IBD, Still's)
3. Cancer (haematological and solid tumours)
4. Medication-related (drug fever, vaccines, biologics)
5. Endocrine disorders (thyroid storm, hyperthyroidism, adrenal insufficiency)
6. Intrinsic hypothalamic malfunction (rare)

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SECTION 6: CLINICAL APPROACH - HISTORY

1. Characterize the Fever

• Onset: Abrupt (bacterial, malaria) vs. insidious (TB, typhoid, endocarditis)
• Duration: Acute (<7 days), subacute (1-4 weeks), chronic (>1 month, FUO territory)
• Pattern (has limited but real diagnostic value):
  • Continuous/sustained: Typhoid, lobar pneumonia, UTI
  • Remittent: Most infections - daily fluctuations >1°C but never reaches normal
  • Intermittent (quotidian): Daily spikes with normal baseline - pyogenic abscess, Still's disease
  • Tertian (every 48h): P. vivax, P. ovale
  • Quartan (every 72h): P. malariae
  • Hectic/septic: Large daily swings ≥5°C - seen in severe bacteraemia, TB, lymphoma
  • Pel-Ebstein: Weeks of fever alternating with weeks of afebrile periods - classic for Hodgkin's lymphoma (rarely seen)
  • Relapsing: Recurrent episodes with afebrile intervals - Borrelia (relapsing fever), Brucella, periodic fever syndromes

2. Associated Symptoms - Systematic

• Constitutional: Weight loss (TB, cancer, HIV), night sweats (TB, lymphoma, endocarditis), fatigue, anorexia
• Neurological: Headache, altered consciousness, neck stiffness (meningitis, encephalitis)
• Respiratory: Cough (productive/dry), pleuritic pain, dyspnoea (pneumonia, TB, PE)
• Cardiovascular: Chest pain, palpitations, new murmur symptoms (endocarditis)
• GI: Diarrhoea (enteric infections), abdominal pain, jaundice (hepatitis, cholecystitis, malaria), dysphagia
• Genitourinary: Dysuria, frequency, flank pain (UTI, pyelonephritis)
• Musculoskeletal: Joint pain, swelling, myalgias (septic arthritis, Lyme, viral)
• Skin: Rash, ulcers, track marks
• ENT: Sore throat, earache, sinus pain

3. Epidemiological History - MUST NOT SKIP

• Sick contacts: Respiratory, GI, childhood exanthems
• Travel history: (most critical) Region, duration, type of accommodation, food/water consumption, activities; even remote travel (months earlier) is relevant for TB, leishmaniasis, melioidosis
• Animal exposures: Cattle/sheep (Q fever, brucellosis), birds (psittacosis), rodents (leptospirosis, hantavirus), bats (rabies, Histoplasma), cats (bartonella, toxoplasmosis), dogs (rabies, Pasteurella)
• Insect bites: Mosquitoes (malaria, dengue, chikungunya, West Nile, Zika), ticks (Lyme, RMSF, ehrlichiosis, babesiosis, CCHF), fleas (plague, murine typhus), mites (scrub typhus), sandflies (leishmaniasis)
• Occupational hazard: Farmers (Q fever, brucellosis), slaughterhouse workers, healthcare workers (TB, COVID), forest workers (Lyme, tick-borne encephalitis)
• Sexual history: HIV, syphilis, gonorrhoea, hepatitis B
• IV drug use: Endocarditis, septic emboli, HIV, hepatitis B/C
• Food history: Unpasteurised dairy (brucellosis, listeria), undercooked meat (toxoplasma, E. coli O157), raw seafood (Vibrio, hepatitis A), raw eggs (Salmonella)
• Immunisations: Documented vaccinations (MMR, typhoid, hepatitis A/B, yellow fever, meningococcal, influenza)

4. Medical History

• Past infections: TB, HIV, recurrent URTIs
• Comorbidities: Diabetes (susceptibility to infections), cardiac valve disease (endocarditis risk), liver cirrhosis (spontaneous bacterial peritonitis), CKD, asplenia
• Recent procedures: Surgery, dental work, catheterisation, bronchoscopy, endoscopy (bacteraemia, seeding prosthetic material)
• Hospitalisation history

5. Medications - Drug Fever

• Virtually any drug can cause fever, even after prolonged use
• Most common culprits: allopurinol, carbamazepine, lamotrigine, phenytoin, sulfasalazine, furosemide, vancomycin, β-lactam antibiotics, sulfonamides, minocycline, isoniazid
• Drug fever may be accompanied by eosinophilia, lymphadenopathy (DRESS/DIHS)
• Test: Fever should resolve within 72 hours of stopping the suspected drug; if it persists beyond 72h, drug fever is unlikely

6. Blunted Febrile Response - At-Risk Groups

• Newborns
• Elderly patients
• Chronic hepatic failure patients
• Chronic renal failure patients
• Patients on glucocorticoids
• Patients on anticytokine therapy (anti-TNF, anti-IL-1, anti-IL-6, anti-IL-17, anti-IL-12/23)

For anticytokine patients: Low-grade fever should be treated with the same urgency as high fever. Latent TB can disseminate on anti-TNF therapy. Anti-IL-17 in psoriasis increases risk of systemic candidiasis.

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SECTION 7: PHYSICAL EXAMINATION

Vital Signs and General

• Temperature: Document exact value, site measured, time of day
• Pulse: Tachycardia expected; if absent (relative bradycardia/"Faget's sign") → typhoid, leptospirosis, rickettsia, dengue, legionellosis, babesiosis, brucellosis, drug fever
• Blood pressure: Hypotension → septic shock, severe dengue; relative hypotension from vasodilation
• Respiratory rate: Tachypnoea → pneumonia, ARDS, metabolic acidosis (sepsis)
• SpO2: Decreased → respiratory involvement, sepsis

Systematic Examination

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SECTION 8: LABORATORY INVESTIGATIONS

Baseline (Obligatory) Tests

Why NOT to Measure Circulating Cytokines (Harrison's)

When to Use Procalcitonin

• Useful for distinguishing bacterial from viral infection (sensitivity ~77%, specificity ~79% for bacteraemia)
• High PCT favours bacterial sepsis; normal PCT argues against serious bacterial infection
• Limitation: Can be elevated in non-infectious conditions (pancreatitis, severe trauma, major surgery)

Advanced/Directed Tests (Based on Clinical Clues)

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SECTION 9: FEVER WITH RASH - DETAILED APPROACH

Key History for Fever + Rash

• Immune status and medications (previous month)
• Travel history
• Vaccination status
• Animal/arthropod bites
• Recent dietary exposures
• Cardiac abnormalities / prosthetic material
• Sexual exposures
• Site of rash onset, direction of spread, and rate of spread - this is highly discriminating

Rash Characterization - Morphology (Harrison's)

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Classification by Rash Pattern (Harrison's Table 21-1)

A. Centrally Distributed Maculopapular Eruptions

B. Peripheral Eruptions (Acral Distribution)

C. Confluent Desquamative Erythemas

D. Vesiculobullous Eruptions

E. Urticarial Eruptions

• Viral infection (hepatitis B prodrome, EBV, CMV)
• Drug reaction
• Serum sickness

F. Nodular Eruptions

• Blastomycosis, Cryptococcus, Histoplasma, Nocardia, NTM
• Erythema nodosum (Streptococcus, TB, sarcoid, IBD)
• Sweet syndrome (febrile neutrophilic dermatosis - malignancy or infection)

G. Purpuric/Petechial Eruptions - LIFE-THREATENING - MUST ACT FAST

H. Eschar

• Scrub typhus (Orientia tsutsugamushi) - bite site in groin, axilla, behind ear
• RMSF (rarely)
• Tularemia
• Anthrax
• Cutaneous leishmaniasis

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SECTION 10: FEVER OF UNKNOWN ORIGIN (FUO)

Updated Definition (Harrison's 22E, 2025)

1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Illness duration of at least 3 weeks
3. No known immunocompromised state (immunocompromised patients require a separate more aggressive approach)

Original Petersdorf-Beeson 1961 definition also required "≥1 week of inpatient evaluation without diagnosis" - current definition no longer mandates inpatient evaluation, reflecting modern outpatient diagnostics.

Why the FUO Landscape Has Changed Since 1960s

• Intra-abdominal abscesses and tumors now detected earlier (CT, US)
• Infective endocarditis less common cause (better blood cultures, echocardiography)
• New diagnoses added: Acute HIV, autoinflammatory diseases (unknown in 1960s)
• Proportion without final diagnosis now higher in Western Europe vs. Asia (2-5x)

Etiology of FUO - Data from Large International Studies (Harrison's Table 22-1, 2005-2023)

Causes of FUO - Comprehensive List (Harrison's Table 22-2)

• Bacterial (non-specific): Abdominal/pelvic/hepatic/brain abscess, endocarditis, osteomyelitis, spondylodiscitis, infected vascular catheter/prosthesis, epidural abscess, septic phlebitis
• Bacterial (specific): Tuberculosis (most common globally), brucellosis, bartonellosis, Lyme disease, leptospirosis, Q fever, rickettsiosis, tularemia, melioidosis, actinomycosis, nocardiosis, legionellosis, listeriosis, ehrlichiosis, Salmonella, NTM
• Viral: HIV, EBV, CMV, adenovirus, parvovirus B19
• Fungal: Histoplasma, Aspergillus, Blastomyces, Candida, Cryptococcus
• Parasitic: Visceral leishmaniasis (kala-azar), toxoplasmosis, malaria (early), schistosomiasis, toxocariasis

• Adult-onset Still's disease - quotidian fever, salmon-colored rash, arthritis, extremely high ferritin
• SLE - multisystem, ANA, complement consumption
• Vasculitis: Giant cell arteritis (elderly), polyarteritis nodosa, ANCA-associated vasculitis, Takayasu
• Rheumatoid arthritis (systemic)
• IBD (Crohn's disease, UC)
• Sarcoidosis
• Autoinflammatory diseases: PFAPA, TRAPS, CAPS, FMF (periodic fever syndromes)
• Castleman disease
• IgG4-related disease

• Lymphoma (Hodgkin's and NHL - most common haematological)
• Leukemia (AML, ALL, CLL)
• Renal cell carcinoma (classic fever-causing solid tumor)
• Hepatocellular carcinoma
• Atrial myxoma
• CNS tumors
• Metastatic carcinoma

• Drug fever (any drug; stop and observe)
• Factitious fever (patient manipulates thermometer)
• Benign/exercise-induced hyperthermia (no CRP/ESR elevation; possibly post-viral: EBV, Q-fever, COVID-19 long fever)
• Thyroiditis (subacute or chronic)
• Adrenal insufficiency
• Haematoma (resorbing)
• Pulmonary embolism (recurrent)
• Periodic fever syndromes

FUO - Structured Diagnostic Approach (Harrison's Figure 22-1 framework)

Step 1: Complete and Repeated History + Physical Exam

• Fever pattern (continuous vs. recurrent)
• Duration and previous medical history
• Complete drug list (including OTC, supplements)
• Family history
• Sexual history
• Country of origin
• Recent AND remote travel
• Environmental/occupational/hobby exposures
• Animal contacts
• Examine: Eyes (uveitis → sarcoid, Behçet; exudates → endocarditis), lymph nodes, temporal arteries (GCA), liver, spleen, sites of previous surgery, entire skin surface, mucous membranes

Stop antibiotics and glucocorticoids before further workup: Steroids reduce lymph node size regardless of cause (misleading); antibiotics render blood cultures sterile.

Step 2: Obligatory Investigations (All FUO Patients)

• CBC with differential
• CRP + ESR
• LFTs, renal function, electrolytes
• LDH, uric acid, ferritin
• Serum protein electrophoresis (SPEP)
• ANA, RF
• Blood cultures × 3 sets (prolonged incubation for HACEK, Brucella)
• HIV serology (4th gen Ag/Ab)
• TB IGRA or TST
• EBV, CMV serology
• CMV/EBV PCR if immunocompromised
• Urinalysis + urine culture
• Serum cryoglobulins (valuable screening despite non-specific)
• Abdominal ultrasound (preferred over CT initially - low cost, no radiation)
• Chest X-ray (obligatory, despite limitations)

Multiple blood cultures must be held long enough for fastidious organisms (HACEK group). Inform microbiology lab when unusual organisms are suspected; use specialized media for Histoplasma, Legionella, Brucella.

More than 3 blood cultures or more than one urine culture (in absence of PDCs) adds little diagnostic yield and is not recommended.

Step 3: Imaging

1. CT chest/abdomen/pelvis - first advanced imaging step
   • Detects abscesses, masses, lymphadenopathy, fluid collections
2. 18F-FDG-PET/CT - high-yield in FUO
   • Identifies metabolically active foci of infection, inflammation, or malignancy
   • Particularly useful for: large-vessel vasculitis (GCA, Takayasu), lymphoma, occult abscesses, spondylodiscitis, infected prostheses
   • Important caution: Glucocorticoids rapidly eradicate pathological FDG uptake - stop steroids before performing PET/CT
   • Normal PET/CT → associated with higher rates of spontaneous fever resolution
   • Cost-effective if used early (reduces hospitalisation days, avoids unnecessary tests)
   • Repeating PET/CT rarely adds value unless new symptoms emerge
3. Echocardiography - TTE first, then TOE if suspicion for endocarditis remains
4. MRI - vertebral osteomyelitis, spondylodiscitis, CNS, vascular lesions; full-body MRI showing comparable diagnostic yield to PET/CT in early studies
5. Scintigraphy (when PET/CT unavailable):
   • Gallium-67: diagnostic yield 21-54%
   • 111In-leucocyte scintigraphy: identifies cause in ~20% of cases
   • Both inferior to PET/CT

Step 4: Later-Stage (PDC-Driven) Investigations

• Bone marrow biopsy: For haematological malignancy, granulomatous disease (TB, brucellosis, histoplasmosis), leishmaniasis
• Liver biopsy: Granulomatous hepatitis (TB, Q fever, sarcoid), hepatic lymphoma
• Lymph node biopsy: Accessible nodes >1 cm; histology + culture
• Temporal artery biopsy: Elderly patients with GCA features (temporal pain, jaw claudication, high ESR)
• Skin biopsy: Any suspicious skin lesion
• Diagnostic laparoscopy/laparotomy: If all else fails and patient deteriorating

Prognosis of FUO

• Depends on underlying diagnosis
• In undiagnosed FUO: Large cohort studies show majority resolve spontaneously
• Mortality ≤8% over several years of follow-up in undiagnosed cases
• Normal 18F-FDG-PET/CT predicts higher rate of spontaneous resolution

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SECTION 11: NEUTROPENIC FEVER

Definition

• Single oral temperature ≥38.3°C (101°F), OR
• Temperature ≥38.0°C (100.4°F) sustained over 1 hour
• PLUS ANC <500 cells/μL OR expected to decrease to <500/μL within 48 hours

Pathophysiology

• Chemotherapy disrupts mucosal barriers and depletes neutrophils
• Most organisms are from the patient's own microbiome (skin and bowel flora)
• Infection documented in only ~40% by standard methods; newer plasma cell-free DNA PCR identifies a bacterial etiology in the majority
• During neutropenia: localizing signs may be subtle or absent; infections progress very quickly
• Similar management even without fever if infection is suspected (unexplained pain, tenderness, erythema)

First Episode Management

1. Swift history + physical exam focused on portals of entry:
   • Central venous catheter exit site
   • Oral cavity (mucositis)
   • Perianal area
2. Blood cultures (peripheral + through all CVC lumens)
3. Empirical antibiotics within 1 hour

• Ceftazidime
• Cefepime
• Imipenem
• Meropenem
• Piperacillin-tazobactam

• Sepsis / haemodynamic instability
• Clinically evident soft tissue infection
• Clinically suspected catheter exit site infection
• Pneumonia
• Severe mucositis (especially if ceftazidime is used, due to viridans streptococcal risk)
• Known MRSA or penicillin-resistant pneumococcal carrier

Meta-analysis shows routine vancomycin in the initial regimen does NOT improve outcomes but causes more nephrotoxicity.

• Vancomycin + meropenem ± aminoglycoside ± echinocandin (if Candida risk)

Fever Resolution and De-escalation

• Fever resolves within 24-72 hours in most cases after antibiotics
• If a specific pathogen is isolated: treat for appropriate duration for that infection
• If no pathogen found and fever resolves: recent evidence supports de-escalation to prophylaxis or discontinuation if clinically stable (vs. historical practice of continuing until ANC recovery)

Risk Stratification

• Score ≥21 = low risk → oral antibiotics as outpatient (ciprofloxacin + amoxicillin-clavulanate)
• Score <21 = high risk → IV antibiotics inpatient

Outpatient Therapy for Low-Risk NF (Harrison's)

• Oral ciprofloxacin + amoxicillin-clavulanate is the standard regimen
• Patient must meet MASCC criteria and be able to swallow; close follow-up mandatory

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SECTION 12: FEVER IN THE ICU - 2024 SCCM/IDSA GUIDELINES

Background

• Fever occurs in 26-88% of adult ICU patients
• Updated 2024 guidelines (O'Grady NP, Deresinski S et al. Crit Care Med. 2023 Nov;51(11):1570-1586)
• Replaces 2008 guidelines
• Uses GRADE methodology: 1 strong recommendation, 12 weak recommendations, 9 best practice statements; 4 areas with insufficient evidence

Definition of Fever in the ICU

• Temperature ≥38.3°C (101°F) is the standard threshold used in most guidelines
• Non-invasive temperature measurement (tympanic, temporal) acceptable for screening; core temperature monitoring preferred in selected patients (e.g., with targeted temperature management)

2024 SCCM/IDSA Recommendations

I. Temperature Measurement

• Weak recommendation: For critically ill patients with fever, central temperature monitoring should be considered in selected patients

II. Antipyretic Treatment

1. Weak recommendation (Moderate QoE): For critically ill patients with fever, avoid routine use of antipyretics for the sole purpose of reducing temperature
   • Rationale: Fever may be beneficial (immune response); routine antipyretics have not been shown to improve outcomes in ICU patients
2. Weak recommendation (Low QoE): For patients who value comfort (symptom relief), prefer antipyretic medications over non-pharmacological cooling methods
   • Rationale: Pharmacological methods (acetaminophen) better tolerated and equally or more effective for comfort

III. Imaging

1. Best practice statement: For any patient developing fever in the ICU, perform a chest radiograph
2. Thoracic bedside ultrasound may supplement CXR

IV. Blood Cultures

1. Best practice statement: In adult ICU patients, collect at least two sets of blood cultures (ideally 60 mL total blood volume), from different anatomical sites, without a time interval between sets
2. Best practice statement: For fever with a central venous catheter (CVC), collect simultaneous CVC + peripheral blood cultures to allow differential time-to-positivity (DTP) calculation
   • DTP >120 minutes between CVC and peripheral → suggests catheter-related bloodstream infection (CRBSI)
3. Best practice statement: When CVC cultures are collected, sample at least two lumens
4. Weak recommendation (Very Low QoE): If rapid molecular tests on blood are used, they should only be used with concomitant standard blood cultures (not as replacement)

V. Urine Cultures

• Best practice statement: For febrile ICU patients with pyuria and suspected UTI, replace the urinary catheter first and obtain urine culture from the newly placed catheter

VI. Key Principles (Expert Consensus)

• Antimicrobial stewardship: Don't reflexively start broad-spectrum antibiotics for all ICU fevers - non-infectious causes are common
• Non-infectious causes of ICU fever to consider actively:
  • Drug fever (antibiotics, phenytoin, heparin, vancomycin)
  • Transfusion reaction
  • Venous thromboembolism (DVT/PE)
  • Acalculous cholecystitis
  • Systemic inflammatory response (SIRS - post-surgery, pancreatitis)
  • Adrenal insufficiency
  • Subarachnoid or CNS haemorrhage (central fever)
  • Wound haematoma resorption

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SECTION 13: FEVER IN SPECIAL POPULATIONS

Fever in the Elderly

• Mean temperature lower by 0.02°C per decade of age
• Clinical signs of infection (fever, leukocytosis, localizing symptoms) can all be absent or blunted
• Normal temperature does not exclude serious infection
• Higher thresholds needed: even a single oral temperature >37.2°C in a nursing home resident warrants evaluation per some guidelines
• Atypical presentations: new confusion, falls, functional decline without fever

Fever in Pregnancy

• Fever in first trimester carries teratogenic risk (neural tube defects described with prolonged hyperthermia)
• Antipyretic treatment with acetaminophen is recommended to reduce teratogenic risk
• NSAIDs - caution in later pregnancy (premature closure of ductus arteriosus)
• Consider listeriosis, UTI/pyelonephritis, viral infections

Fever in Returning Traveller

• Malaria must be excluded in any febrile patient returning from an endemic area within 3 months - this is urgent
• Key investigations: thick and thin blood films × 3 consecutive days; malaria RDT; PCR if films negative but high suspicion
• Differential by geography:
  • Sub-Saharan Africa: malaria, typhoid, HIV, dengue
  • Southeast Asia: dengue, malaria, typhoid, scrub typhus, melioidosis
  • Central/South America: dengue, malaria, Zika, chikungunya, leptospirosis
  • South Asia (Indian subcontinent): typhoid, dengue, malaria, leptospirosis
  • Middle East/Mediterranean: brucellosis, Q fever, leishmaniasis

Fever in Immunocompromised (Non-Neutropenic)

• Broader differential: opportunistic infections + usual infections
• Pathogen determined by type of immune defect:

Fever in the Post-operative Patient

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SECTION 14: TREATMENT OF FEVER

When to Treat Fever

• Patients with impaired cardiac function - fever increases O2 demand by 13% per 1°C above 37°C; may precipitate cardiac ischaemia
• Patients with impaired pulmonary function - respiratory demand increases with fever
• Patients with CNS dysfunction - high fever worsens neuronal injury
• Children with history of febrile or non-febrile seizures - treat aggressively (note: no correlation between absolute temperature level and seizure onset in susceptible children, but fever reduction is still standard)
• Hyperpyrexia (>41.5°C) - mandatory cooling
• Pregnancy - first trimester hyperthermia is teratogenic
• Patient comfort - fever causes headache, myalgias, arthralgias; antipyretics improve quality of life

• Mild infectious illness in otherwise healthy adults (fever may be beneficial)
• ICU patients without the above indications (2024 SCCM/IDSA: weak recommendation against routine antipyretics for the sole purpose of temperature reduction)

Antipyretic Agents

Aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and GI tract. Therefore, acetaminophen is preferred as the first-line antipyretic.

Physical Cooling Methods

• Indicated for hyperpyrexia (>41.5°C) as adjunct to pharmacological treatment
• Cooling blankets may facilitate temperature reduction
• Critical rule (Harrison's): Cooling blankets should NOT be used without oral antipyretics - without antipyretics, the hypothalamic set point remains elevated and the patient shivers, which counterproductively generates more heat
• In hyperpyrexia with CNS disease or trauma: reducing core temperature mitigates detrimental effects of high temperature on the brain

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SECTION 15: MASTER ALGORITHM - APPROACH TO FEVER

PATIENT WITH ELEVATED TEMPERATURE
          │
          ▼
┌─────────────────────────────────────┐
│ STEP 1: FEVER vs. HYPERTHERMIA?    │
│ - Set point raised = FEVER          │
│ - Set point normal = HYPERTHERMIA   │
│ - Responds to antipyretics = FEVER  │
└─────────────────┬───────────────────┘
                  │
    ┌─────────────┴───────────────┐
    │                             │
  FEVER                     HYPERTHERMIA
    │                       → Physical cooling
    │                       → Specific antidotes
    │                         (dantrolene, cyproheptadine)
    ▼
┌─────────────────────────────────────────┐
│ STEP 2: RISK STRATIFICATION             │
│ Is this patient at risk for:             │
│ - Blunted fever? (elderly, steroids,     │
│   anti-cytokines, renal/hepatic failure)│
│ - Immunosuppression / neutropenia?      │
│ - Sepsis / haemodynamic instability?    │
└─────────────────┬───────────────────────┘
                  │
    ┌─────────────┴──────────────────────┐
    │                                    │
  STABLE                            UNSTABLE
    │                                    │
    ▼                                    ▼
FULL HISTORY                     RESUSCITATE + SEPSIS PROTOCOL
    │                            Blood cultures → Antibiotics <1h
    ▼
┌──────────────────────────────────────────────┐
│ STEP 3: HISTORY                               │
│ - Fever onset, duration, pattern             │
│ - Associated symptoms by system              │
│ - Epidemiology: travel, animals, insects,    │
│   sexual hx, food, occupation, drugs         │
│ - Medications (drug fever?)                  │
│ - Vaccinations, comorbidities, procedures    │
└─────────────────┬────────────────────────────┘
                  ▼
┌──────────────────────────────────────────────┐
│ STEP 4: PHYSICAL EXAMINATION                  │
│ Complete head-to-toe with focus on:          │
│ Skin (rash), nodes, heart (murmur),         │
│ abdomen (hepatosplenomegaly), joints,        │
│ neurological, temporal arteries, catheter   │
└─────────────────┬────────────────────────────┘
                  ▼
        Does a localizing source emerge?
              │             │
             YES            NO
              │             │
              ▼             ▼
        Targeted        Baseline Labs + Cultures
        workup &        CXR, Urine, CBC, CRP, ESR,
        therapy         Blood cultures × 2 sets
                             │
                    ┌────────┴────────┐
                    │                 │
              ACUTE FEVER          FEVER > 3 WEEKS
              <3 weeks             + No diagnosis
                    │                 │
             Consider:           FUO WORKUP:
             - Infection          Step 1-4 protocol
             - Drug fever         PET/CT, bone marrow
             - Post-infectious    biopsy as indicated
             - Rheumatological
                    │
          ┌─────────┴───────────┐
          │                     │
      FEVER + RASH          NEUTROPENIC
          │                     │
    Classify rash:          Empirical ABx
    - Petechiae/purpura      within 1 hour
      → EMERGENCY            (carbapenem or
    - Eschar → rickettsial    anti-pseudomonal
    - Palms+soles             cephalosporin
      → RMSF/syphilis/        monotherapy)
        endocarditis

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QUICK REFERENCE SUMMARY TABLE

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• Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw-Hill) - Chapters 20, 21, 22, and 79 (Dinarello, Surana, Kaye & Kaye, Rovers)
• 2024 SCCM/IDSA Joint Guidelines for Evaluating New Fever in Adult ICU Patients (O'Grady NP, Deresinski S et al. Crit Care Med. 2023;51:1570-1586) - replaces 2008 guidelines; GRADE-based; 1 strong + 12 weak recommendations + 9 best practice statements