Fever/chills
Fever is an elevation of body temperature above the normal set point, often accompanied by chills (rigors), typically resulting from the release of pyrogenic cytokines in response to infection, inflammation, or other pathological processes.
Fever and Chills
Let's start from the basics. Fever (pyrexia) is an elevation of body temperature above the normal set-point, mediated by the hypothalamus. It is fundamentally different from hyperthermia.
- Fever: The hypothalamic thermoregulatory set-point is raised by the action of pyrogens. The body actively generates and conserves heat (through vasoconstriction, shivering, behavioural changes) to reach this new, higher set-point. Because the set-point is elevated, the body "thinks" it is cold — hence chills.
- Hyperthermia: The set-point is normal but heat gain overwhelms heat dissipation (e.g. heat stroke, malignant hyperthermia, neuroleptic malignant syndrome). The thermoregulatory system is trying to cool down but failing. Antipyretics do not work in hyperthermia because there is no pyrogen-driven set-point change.
Normal body temperature: 36.1–37.2°C (oral), with diurnal variation — lowest at ~06:00 (nadir) and highest at ~16:00–18:00 (peak), amplitude ~0.5°C. This is driven by the circadian cortisol rhythm.
Fever thresholds (commonly used):
- > 38.0°C (oral) — general clinical threshold
- > 38.3°C — used in fever of unknown origin (FUO) definition and neutropenic fever definition [1][2]
- > 38.0°C sustained for > 1 hour — alternative criterion for neutropenic fever [2]
Chills are the subjective sensation of cold accompanied by involuntary muscle contractions (shivering). Rigors are severe, uncontrollable shaking episodes. These occur because the thermoregulatory set-point has been acutely raised, creating a gap between the current body temperature and the new set-point — the body responds with vasoconstriction (cold peripheries, pallor) and skeletal muscle contraction (shivering/rigors) to generate heat.
Key distinction: Chills/rigors = set-point has been raised → body is actively heating. Night sweats/defervescence = set-point has been lowered back → body is actively cooling (vasodilation, sweating) to reach the lower set-point.
Hypothermia as a Warning Sign
Temperature < 36°C (hypothermia) can also indicate severe infection/sepsis, particularly in the elderly, neonates, immunocompromised, and those with chronic liver or renal disease. Do NOT dismiss a low temperature in a sick patient — it may indicate a worse prognosis than fever. [1]
Fever is one of the most common presenting complaints across all age groups and clinical settings.
- Primary care: Accounts for a substantial proportion of GP visits, particularly in paediatrics (up to 20–30% of paediatric consultations)
- Emergency department: One of the top 5 presenting complaints
- Hospital inpatients: Post-operative fever is extremely common (see below); nosocomial fever affects 20–30% of ICU patients
- Fever in the elderly is sepsis until proved otherwise (especially lungs and urinary tract) [3]
- Hong Kong context: High population density, subtropical climate, and significant travel hub status mean that tropical infections (dengue, typhoid, malaria from travel), TB (prevalence ~60/100,000 — one of the highest in developed regions), and viral respiratory infections (influenza, COVID-19, RSV) are common causes of fever. Klebsiella pneumoniae liver abscess in diabetic patients is a particularly important East Asian entity [4]
Anatomy and Physiology of Thermoregulation
The preoptic area of the anterior hypothalamus serves as the body's thermostat. It:
- Receives afferent input from peripheral thermoreceptors (skin, deep tissue) and central thermoreceptors (hypothalamic neurons themselves sensing blood temperature)
- Compares current body temperature against the set-point
- Initiates efferent responses:
- Too cold (current temp < set-point): Sympathetic activation → cutaneous vasoconstriction, piloerection, shivering thermogenesis, behavioural changes (seeking warmth), non-shivering thermogenesis (brown fat, especially in neonates)
- Too hot (current temp > set-point): Cutaneous vasodilation, sweating, behavioural changes (seeking cool)
This is the central mechanism of fever and explains everything about how infection → chills/fever:
Why this matters clinically:
- NSAIDs/Paracetamol work by inhibiting COX enzymes → ↓PGE2 production → lowering the set-point back to normal → body then vasodilates and sweats to cool down (defervescence). This is why antipyretics are useless in true hyperthermia (no PGE2-mediated set-point elevation).
- Corticosteroids are potent antipyretics because they inhibit phospholipase A2 → ↓arachidonic acid release → ↓PGE2. This is why immunosuppressed patients on steroids may not mount a fever even with severe infection.
Fever is an adaptive response:
- Many pathogens replicate optimally at 37°C; elevated temperatures reduce their growth
- Higher temperatures enhance immune function: ↑neutrophil migration, ↑phagocytosis, ↑T-cell proliferation, ↑interferon activity
- The metabolic cost is significant (~10–12.5% ↑O₂ consumption per 1°C rise), which is why fever can be detrimental in those with limited cardiac or respiratory reserve
Etiology of Fever/Chills
The causes of fever are vast. A systematic approach is essential. The most practical framework considers the clinical setting.
Infection is the most common cause of fever across all settings. Virtually any infection can cause fever, but certain patterns are high-yield:
| System | Common Causes | Hong Kong/Regional Considerations |
|---|---|---|
| Respiratory | Pneumonia (CAP, HAP), TB, influenza, COVID-19, sinusitis, pharyngitis, lung abscess | TB is highly prevalent in HK (~60/100k). Pneumonia accounts for 17.6% of deaths in HK (2nd leading cause) [5] |
| Urinary | Cystitis, pyelonephritis, prostatitis | Most common cause of fever in elderly; often presents atypically [6] |
| Abdominal/GI | Appendicitis, cholecystitis, cholangitis, liver abscess, diverticulitis, peritonitis, gastroenteritis | Klebsiella pneumoniae liver abscess in DM patients is a classic East Asian entity [4][7]. Amoebic liver abscess from E. histolytica — consider travel to endemic areas [7] |
| CNS | Meningitis, encephalitis, brain abscess | S. suis from raw pork exposure in HK/South China [8] |
| Cardiac | Infective endocarditis, myocarditis, pericarditis | Viral myocarditis — enterovirus, parvovirus B19, HHV6 [9]. IE: S. viridans (native valve), S. aureus (acute/IVDU) |
| Skin/Soft tissue | Cellulitis, erysipelas, necrotising fasciitis, wound infection | β-haemolytic strep (commonest for cellulitis/erysipelas), S. aureus [10] |
| Bone/Joint | Septic arthritis, osteomyelitis | S. aureus most common in adults; N. gonorrhoeae in sexually active young adults [11] |
| Specific tropical/travel | Dengue, malaria, typhoid, scrub typhus, melioidosis | Dengue is endemic in HK (local transmission). Malaria — travel to SE Asia/Africa |
| Viral | EBV (infectious mononucleosis), CMV, HIV seroconversion, hepatitis A/B/C/E | Hepatitis B is highly prevalent in HK (~7–8% chronic carriers) |
The 'Non-Infectious Fever' Trap
Always exclude infection first before attributing fever to a non-infectious cause. A common exam mistake is premature closure — labelling a fever as "drug fever" when there is an underlying abscess.
1. Autoimmune/Inflammatory
- Connective tissue disorders: SLE, RA, adult-onset Still's disease (classic cause of high spiking quotidian fever with salmon-coloured evanescent rash), vasculitis (GPA, PAN, GCA/PMR)
- Connective tissue disorder (e.g. rheumatoid arthritis, systemic lupus erythematosus) [3]
- Sarcoidosis [3]
- Inflammatory bowel disease: Crohn's disease can present with fever [3]
- Crystal arthropathies: Gout, pseudogout — acute flares cause fever
2. Neoplastic
- Haematological malignancies: Lymphoma (Pel-Ebstein fever — cyclical fever in Hodgkin lymphoma, though this is rare), leukaemia, myelodysplastic syndrome
- Solid tumours: Renal cell carcinoma (classic), hepatocellular carcinoma, atrial myxoma, colorectal cancer with occult abscess
- Tumour fever is due to cytokine release (IL-1, IL-6, TNF-α) from tumour cells or surrounding immune cells
3. Drug Fever
- Drug idiosyncrasies [3]
- Mechanism: Usually a type IV hypersensitivity reaction — takes 7–10 days for sensitization, so typically occurs 7–10 days after starting a new drug
- Common culprits: Antibiotics (β-lactams, sulfonamides, vancomycin), anticonvulsants (phenytoin, carbamazepine), allopurinol, heparin, procainamide
- Patient may appear "paradoxically well" for the degree of fever
- Classically resolves within 48–72 hours of stopping the offending drug
4. Thromboembolic
- DVT/PE can cause fever (due to tissue necrosis and inflammatory mediator release)
- DVT/PE: first sign may be unexplained tachycardia; 60–80% clinically silent [12]
5. Endocrine
- Thyroid storm / thyrotoxicosis: Excess thyroid hormone → ↑metabolic rate → ↑heat production. This is technically a mix of true fever and hyperthermia.
- Phaeochromocytoma: Catecholamine excess → ↑metabolic rate
- Adrenal crisis (Addisonian crisis): Can present with fever, hypotension, and shock
- Wonky glands: hyperthyroidism, phaeochromocytoma, Addisonian crisis [12]
6. Other
- Factitious fever: Self-induced or fabricated; consider in young healthcare workers with atypical fever patterns and no objective cause [3]
- Transfusion reactions: Febrile non-haemolytic transfusion reaction (FNHTR) — reaction to donor leukocyte antigens (cytokines accumulate in stored blood products), occurs 30 min–2 hours post-transfusion. Allergic transfusion reaction — reaction to donor plasma antigens, occurs early [12]
- Tissue necrosis: MI, rhabdomyolysis, haemolysis, haematoma, pulmonary infarction — all release intracellular contents that act as endogenous pyrogens
Post-operative fever is defined as temperature > 38°C on 2 consecutive post-operative days OR > 39°C on any 1 post-operative day [12]
The classic mnemonic is the "5 W's" (or extended "7 W's"), organized by timing:
| Timing | W | Cause | Pathophysiology |
|---|---|---|---|
| Day 0–2 | Wind | Atelectasis | Post-anaesthesia ↓deep breathing → alveolar collapse → cytokine release from atelectatic lung. Note: the causal link between atelectasis and fever is debated, but this remains the classic teaching [12] |
| Day 3–5 | Water | UTI | Catheter-associated; biofilm formation on catheter surface → ascending infection [12] |
| Day 3–5 | Water | Anastomotic leak | Bowel content spillage → peritonitis → massive inflammatory response [12] |
| Day 5–7 | Wound | Wound infection / SSI | Bacterial contamination during surgery → incubation period → cellulitis/abscess at surgical site [12] |
| Day 5+ | Walking | DVT/PE | Venous stasis + hypercoagulability (Virchow's triad) → thrombus formation → tissue necrosis and inflammation [12] |
| Day 7–10 | Wonder drugs | Drug fever | Type IV hypersensitivity — 7–10 days for antibody formation; common agents include antibiotics. Malignant hyperthermia: with FHx, can be delayed up to 24 hours post-op, common agents include suxamethonium. NMS: antiemetic drugs (e.g. metoclopramide) [12] |
| Any time | Withdrawal | Alcohol withdrawal | Autonomic hyperactivity from abrupt cessation of chronic alcohol use → adrenergic surge |
| Any time | Wonky glands | Adrenal insufficiency, thyrotoxicosis | Cortisol deficiency (Addisonian) or excess thyroid hormone [12] |
| Any time | — | Easily missed: infected central line, C. diff colitis, acute pancreatitis, acalculous cholecystitis [12] | — |
Important Post-Op Fever Points
- Hyperthermia may not be initiated in immunocompromised patients — they may not mount a fever even with severe sepsis [12]
- Hypothermia also indicates severe sepsis [12]
- D-dimer is NOT useful post-operatively — it is elevated from surgery anyway [12]
- Prevention of DVT/PE: Early mobilisation (general), compression stockings/SCD (mechanical), LMWH (pharmacological, rare) [12]
FUO is defined as fever ≥ 38.3°C for at least 3 weeks, without diagnosis after appropriate investigation [3]
Classic categories (Petersdorf & Beeson, updated):
- Infection (~25–30%): TB, abscess (hepatic, pelvic, dental), endocarditis, osteomyelitis
- Neoplasm (~15–20%): Lymphoma, leukaemia, RCC, HCC, atrial myxoma
- Autoimmune/Inflammatory (~15–20%): Adult-onset Still's disease, SLE, vasculitis (GCA/PMR in elderly), sarcoidosis
- Miscellaneous (~10–15%): Drug fever, factitious fever, thyroiditis, recurrent PE, Crohn's
- Up to 20% remain unknown [3]
"Prolonged fever is usually an uncommon presentation of a common disorder (unless recent travel, especially to the tropics)" [3]
Pathophysiology of Fever — Deeper Dive
-
Exogenous pyrogens are pathogen-associated molecular patterns (PAMPs) — e.g. LPS (Gram-negative), lipoteichoic acid (Gram-positive), peptidoglycan, viral dsRNA, fungal β-glucan — and damage-associated molecular patterns (DAMPs) from tissue injury (e.g. HMGB1, uric acid crystals, heat shock proteins)
-
These are recognized by pattern recognition receptors (PRRs) on innate immune cells:
- Toll-like receptors (TLRs): TLR4 recognizes LPS, TLR2 recognizes lipoteichoic acid
- NOD-like receptors (NLRs): Intracellular; some form inflammasomes
-
PRR activation triggers NF-κB signalling → transcription and release of endogenous pyrogens (pro-inflammatory cytokines):
- IL-1β (most potent pyrogen)
- IL-6 (also drives acute phase response → ↑CRP, ↑fibrinogen, ↑hepcidin)
- TNF-α
- IFN-γ (especially in viral infections)
-
These cytokines travel via the bloodstream to the organum vasculosum of the lamina terminalis (OVLT) — a circumventricular organ that lacks a blood-brain barrier
-
At the OVLT, cytokines induce COX-2 and microsomal PGE synthase-1 (mPGES-1) in endothelial and perivascular cells → synthesis of PGE₂
-
PGE₂ diffuses into the hypothalamus and binds EP3 receptors on thermoregulatory neurons in the preoptic area → elevation of the thermoregulatory set-point
-
This triggers efferent responses:
- Vasoconstriction (sympathetic, cutaneous) → cold, pale peripheries
- Shivering (somatic motor via hypothalamic efferents) → heat generation
- Behavioural changes → seeking warmth, curling up
- Non-shivering thermogenesis (brown fat — mainly neonates/infants; UCP-1 uncouples oxidative phosphorylation → heat instead of ATP)
-
Body temperature rises until it reaches the new set-point → plateau phase. When the pyrogen stimulus is removed or antipyretics are given → set-point falls → vasodilation + sweating → defervescence
Fever does not occur in isolation. The same cytokines (IL-1, IL-6, TNF-α) that cause fever also drive the acute phase response:
| Feature | Mechanism |
|---|---|
| ↑CRP | IL-6 stimulates hepatic CRP synthesis. CRP is an opsonin and activates complement |
| ↑ESR | ↑fibrinogen and immunoglobulins → ↑rouleaux formation → faster erythrocyte sedimentation |
| ↑Ferritin | Acute phase reactant; also ↑hepcidin (from IL-6) → sequesters iron from pathogens |
| Leukocytosis | IL-1 and G-CSF → bone marrow stimulation; cortisol → demargination of neutrophils |
| ↑Platelets | IL-6 → megakaryocyte stimulation (reactive thrombocytosis) |
| ↓Albumin | Negative acute phase reactant — hepatic synthetic priority shifts to CRP/fibrinogen |
| Anorexia/Malaise | TNF-α (formerly called "cachexin") and IL-1 act centrally on hypothalamus |
| Somnolence | IL-1 promotes slow-wave sleep |
Classification of Fever
| Type | Duration | Common Causes |
|---|---|---|
| Acute | < 7 days | Viral URTI, influenza, acute bacterial infection |
| Subacute | 1–3 weeks | Abscess, TB, IE, typhoid |
| Chronic | > 3 weeks | FUO framework (see above) |
Fever patterns were historically important before the era of antipyretics (which obscure them). They are still taught and occasionally useful:
| Pattern | Description | Classic Association |
|---|---|---|
| Continuous/Sustained | Temperature remains above normal with < 1°C fluctuation | Typhoid fever (in first week), pneumonia |
| Remittent | Temperature fluctuates > 1°C daily but never returns to normal | Most bacterial infections, IE |
| Intermittent | Temperature returns to normal (or below) daily | Abscess, lymphoma, malaria, drug fever |
| Quotidian | Daily spikes (every 24h) | P. falciparum, adult-onset Still's disease, drug fever |
| Tertian | Spikes every 48h (every 3rd day) | P. vivax, P. ovale ("benign tertian") and P. falciparum ("malignant tertian") |
| Quartan | Spikes every 72h (every 4th day) | P. malariae |
| Pel-Ebstein | Cyclical fever (1–2 weeks on, 1–2 weeks off) | Hodgkin lymphoma (rare, likely apocryphal) |
| Spiking/Swinging fever | High spikes with dramatic falls | Liver abscess, septicaemia, empyema [4] |
| Double quotidian | Two daily spikes | Kala-azar (visceral leishmaniasis), adult-onset Still's, drug fever, IE |
| Saddle-back | Fever resolves then recurs | Dengue, polio, yellow fever |
| Grade | Temperature | Significance |
|---|---|---|
| Low-grade | 37.5–38.0°C | Viral infections, chronic inflammation |
| Moderate | 38.1–39.0°C | Most bacterial infections |
| High | 39.1–41.0°C | Severe infection, drug reactions, blood transfusion reactions |
| Hyperpyrexia | > 41.0°C | CNS infections, malignant hyperthermia, heat stroke, drug reactions — medical emergency |
Clinical Features
| Symptom | Pathophysiological Mechanism |
|---|---|
| Fever / feeling hot | PGE₂-mediated elevation of hypothalamic set-point → once body temperature reaches the new set-point, the patient feels hot and flushed (vasodilation phase) |
| Chills / feeling cold | Set-point has been acutely raised but body temperature has not yet reached it → the gap is perceived as "being cold" → triggers heat-conserving mechanisms |
| Rigors (severe shaking) | Intense involuntary skeletal muscle contraction to generate heat rapidly (shivering thermogenesis at maximum intensity). Classically associated with bacteraemia, particularly Gram-negative sepsis, cholangitis, malaria, transfusion reactions, and abscess rupture |
| Sweating / night sweats | Occur during defervescence — set-point returns to normal (pyrogen clearance or antipyretic effect) → current body temperature now exceeds set-point → hypothalamus activates cooling: vasodilation + eccrine sweat gland activation. Night sweats classically associated with TB, lymphoma, brucellosis, IE |
| Malaise / fatigue | TNF-α and IL-1 act on CNS → sickness behaviour; ↑metabolic demand from fever (↑10–12.5% O₂ consumption per °C) depletes energy stores |
| Anorexia | TNF-α (historically called "cachexin") acts on hypothalamic appetite centres → ↓appetite. Evolutionary purpose: to divert metabolic resources away from digestion toward immune function |
| Myalgia / arthralgia | Pro-inflammatory cytokines (especially IL-1, IL-6, TNF-α) → sensitize peripheral nociceptors + ↑PGE₂ production in muscle and joint tissues → aching pain. Also: catabolism of skeletal muscle proteins for gluconeogenesis contributes |
| Headache | Vasodilation of meningeal vessels (PGE₂-mediated) + cytokine-mediated sensitization of trigeminal nociceptors |
| Tachycardia | ↑metabolic rate → ↑O₂ demand → ↑cardiac output (heart rate rises ~8–10 bpm per 1°C rise). Also: sympathetic activation during the chill phase |
| Tachypnoea | ↑CO₂ production from ↑metabolism → ↑respiratory drive; also direct central respiratory stimulation by cytokines |
| Delirium / confusion | Particularly in the elderly, neonates, and those with baseline cognitive impairment. Mechanism: cytokine-mediated disruption of BBB integrity, altered neurotransmitter metabolism (↑tryptophan → serotonin pathway), cerebral metabolic derangement |
| Febrile seizures | In children 6 months–5 years; mechanism not fully understood but likely involves ↑neuronal excitability at elevated temperatures + immature thermoregulatory/seizure threshold + IL-1β acts directly on hippocampal neurons |
| Decreased urine output | Insensible fluid losses ↑ with fever (~200–500 mL/day per °C above normal through sweating and ↑respiratory water loss) → dehydration → pre-renal oliguria |
Relative Bradycardia — A Diagnostic Clue
Normally, heart rate increases ~8–10 bpm for each 1°C rise in temperature. Relative bradycardia (pulse-temperature dissociation) — where the heart rate is inappropriately low for the degree of fever — is a classic clue pointing to specific aetiologies:
- Intracellular organisms: Typhoid (Salmonella typhi), brucellosis, Legionella, Chlamydia psittaci
- Drug fever
- Lymphoma
- CNS lesions (↑ICP — Cushing reflex)
- Factitious fever
Also remember that relative bradycardia can be masked by beta-blockers or rate-limiting medications.
| Sign | Pathophysiological Mechanism |
|---|---|
| Warm, flushed skin (during plateau/defervescence phase) | Cutaneous vasodilation to dissipate heat once the set-point has been reached or is falling |
| Cold, pale peripheries, goosebumps (during chill phase) | Sympathetic-mediated cutaneous vasoconstriction + piloerection (arrector pili muscle contraction — vestigial in humans) to conserve heat while body temperature is rising toward the elevated set-point |
| Diaphoresis (sweating) | Active cooling during defervescence (set-point falling back toward normal) |
| Tachycardia | HR > 90 bpm [1] — compensatory ↑cardiac output for ↑metabolic demand |
| Tachypnoea | RR > 20 breaths/min [1] — compensatory for ↑CO₂ production |
| Hypotension | If sepsis develops: vasodilation from NO release (iNOS induction by TNF-α/IL-1) + ↑capillary permeability → third-space fluid loss → distributive shock. SBP < 90 mmHg or decrease > 40 mmHg from baseline; MAP < 70 mmHg [1] |
| Dry mucous membranes | Dehydration from insensible losses |
| Lymphadenopathy | Reactive hyperplasia of lymphoid tissue in response to local/systemic infection or inflammation |
| Hepatosplenomegaly | Reticuloendothelial system activation (macrophage/Kupffer cell hyperplasia) — seen in disseminated infection, malaria, EBV, haematological malignancy |
| Skin rash | May indicate specific aetiologies: petechiae/purpura (meningococcaemia, DIC), vesicles (varicella, HSV), maculopapular (viral exanthem, drug reaction), erythema nodosum (TB, sarcoidosis, IBD), erythema migrans (Lyme disease) |
| Jaundice | Suggests hepatobiliary source: cholangitis (Charcot's triad: fever + RUQ pain + jaundice), hepatitis, liver abscess; or haemolysis (malaria) [13] |
| Altered mental status | CNS dysfunction in sepsis (septic encephalopathy) [1]; also direct CNS infection (meningitis, encephalitis) |
When fever progresses to sepsis, look for signs of end-organ hypoperfusion [1]:
| System | Early Signs | Late Signs |
|---|---|---|
| Cardiovascular | Warm and flushed skin (vasodilation phase) → bounding pulses | Cool skin, mottling, cyanosis, ↓capillary refill (vasoconstriction, blood redirected to core) [1] |
| Renal | ↓Urine output | Oliguria or anuria [1] |
| GI | ↓Appetite, nausea | Diminished or absent bowel sounds (paralytic ileus from splanchnic hypoperfusion) [1] |
| CNS | Restlessness, agitation | Altered mental status, obtundation [1] |
| Haematological | Leukocytosis | DIC: bleeding, petechiae, prolonged PT/aPTT [1] |
The Clinical Approach to Fever/Chills
The history may need to be repeated for fever cases — important details (travel, exposures, sexual history) may not be volunteered on first questioning [3].
Include past history, occupation, travel history, sexual history, IV drug use (leads to endocarditis and abscesses), animal contact, medication and other relevant factors. Enquire about associated symptoms such as pruritus, a skin rash, abdominal pain and diarrhoea, and weight loss. Note the fever pattern. [3]
| Domain | What to Ask | Why |
|---|---|---|
| Onset and duration | When did it start? Sudden vs gradual? | Acute bacterial infection = sudden onset with rigors; viral = more gradual; chronic fever = TB, lymphoma, autoimmune |
| Pattern | Continuous? Intermittent? Spiking? Cyclical? | See fever pattern table above |
| Severity | Measured temperature? Rigors? | Rigors → bacteraemia, abscess, cholangitis, malaria |
| Associated symptoms | Cough/sputum/SOB? Dysuria/frequency? Abdominal pain? Headache/neck stiffness? Rash? Joint pain? Diarrhoea? | Localizing the source |
| Constitutional symptoms | Weight loss, night sweats, malaise [5] | TB, lymphoma, disseminated malignancy, IE |
| Travel history | Where and when? Duration? Prophylaxis? | Malaria (incubation 7–30+ days), dengue (4–10 days), typhoid (7–14 days), amebiasis |
| Occupation | Healthcare worker? Farmer? Animal handler? | Nosocomial exposure, leptospirosis, brucellosis, Q fever |
| Sexual history | Partners, STI history, HIV risk factors | HIV seroconversion, gonococcal bacteraemia, pelvic inflammatory disease |
| IV drug use | IE (right-sided), hepatitis B/C, skin/soft tissue abscess | |
| Animal contact | Cats, dogs, birds, livestock, raw pork | Cat-scratch disease, leptospirosis, psittacosis, S. suis from raw pork [8], brucellosis |
| Medication history | New drugs in past 2 weeks? Immunosuppressants? | Drug fever (onset 7–10 days), opportunistic infections in immunosuppressed |
| Surgical/procedural history | Recent surgery? Catheter? Central line? | Post-op fever framework (5 W's), CAUTI, CLABSI |
| Immune status | HIV? Transplant? Chemotherapy? Steroids? Splenectomy? | Neutropenic fever, opportunistic infections, encapsulated organisms post-splenectomy |
| Diet | Raw/undercooked food? Unpasteurized dairy? | Hepatitis A/E, listeriosis, brucellosis, amebiasis |
Note general features and vital signs. Check skin (rash, vesicles or nodules), eyes, temporal arteries, sinuses, teeth and oral cavity, heart (note any murmurs), lungs, abdomen (enlarged or tender liver, spleen, kidney), rectal and pelvic examination, lymph nodes (especially cervical), urinalysis. [3]
A systematic head-to-toe examination is essential. The goal is to find the source:
| Area | What to Look For | Diagnostic Significance |
|---|---|---|
| General | Toxic vs well-looking; nutritional status; hydration | Septic patients look "toxic"; factitious fever patients look "paradoxically well" |
| Vital signs | Temperature, HR, RR, BP, SpO₂ | Sepsis screening (qSOFA: RR > 22, sBP < 100, altered GCS) [14] |
| Skin | Rash, petechiae, purpura, vesicles, nodules, surgical wounds, IV cannula sites, pressure ulcers, track marks | Petechiae → meningococcaemia/DIC; vesicles → varicella/HSV; Osler nodes/Janeway lesions → IE; track marks → IVDU |
| Eyes | Conjunctival pallor (anaemia), Roth spots (retinal haemorrhages with white centre → IE), jaundice, endophthalmitis (especially Klebsiella) [7][15] | |
| Temporal arteries | Tenderness, thickening, ↓pulsation | GCA in elderly with new headache + fever + ↑ESR |
| Oral cavity | Dental caries, mucosal ulcers, pharyngeal exudate, candidiasis | Dental abscess → bacteraemia; oral candidiasis → immunosuppression/HIV |
| Sinuses | Tenderness over maxillary/frontal sinuses | Sinusitis |
| Neck | Lymphadenopathy (size, consistency, tenderness, distribution), nuchal rigidity, thyroid enlargement/tenderness | Nuchal rigidity → meningitis; tender thyroid → subacute thyroiditis [16] |
| Heart | New/changing murmur | IE |
| Lungs | Crackles, bronchial breathing, dullness to percussion, ↓air entry | Pneumonia, pleural effusion, empyema |
| Abdomen | Tender hepatomegaly (liver abscess), splenomegaly, Murphy's sign (cholecystitis), RIF tenderness (appendicitis), suprapubic tenderness (cystitis), jaundice | [4] |
| Rectal | Perianal abscess, prostate tenderness (prostatitis) | Especially important in neutropenic patients |
| Pelvic | Cervical motion tenderness, adnexal masses | PID, tubo-ovarian abscess |
| Joints | Hot, swollen, tender joint(s) | Hot, swollen tender joint = septic arthritis until proven otherwise, even without fever [11] |
| Lymph nodes | Generalized vs localized; size; consistency; tenderness | Generalized → EBV, HIV, lymphoma, SLE; localized → local infection, metastatic LN |
| Lines and catheters | Exit site erythema, purulence, tenderness | CLABSI, exit-site infection |
Charcot's Triad and Reynold's Pentad
For acute cholangitis (biliary infection from obstruction + bacterial contamination) [13]:
- Charcot's triad (present in 2/3 of patients): Fever + RUQ pain + Jaundice
- Reynold's pentad (indicates suppurative cholangitis with sepsis): Charcot's triad + Mental obtundation + Hypotension
The basics are: FBE (full blood examination), ESR/CRP, CXR and sinus films, urine MC (microscopy and culture), routine blood chemistry, LFTs, blood culture. [3]
Other tests depend on clinical pointers (e.g. specific organisms, lymph node biopsy, HIV, tuberculosis, connective tissue auto-antibodies). [3]
| Investigation | Rationale |
|---|---|
| FBE/CBC with differential | Leukocytosis (bacterial infection); leukopenia (overwhelming sepsis, viral); left shift (↑bands = immature neutrophils mobilized from marrow); eosinophilia (parasites, drug reaction, vasculitis); lymphocytosis (viral, TB, lymphoma); atypical lymphocytes (EBV); pancytopenia (marrow infiltration, overwhelming sepsis) |
| CRP | Acute phase reactant; rises within 6–8 hours of inflammation, peaks at 48h. Non-specific but useful for monitoring response to treatment. Very high CRP (> 100) more suggestive of bacterial than viral infection |
| ESR | Slower to rise (days) and fall than CRP. Useful for chronic inflammation (GCA, TB, IE). Very high ESR (> 100) → consider myeloma, TB, abscess, lymphoma, autoimmune disease |
| Procalcitonin (PCT) | More specific for bacterial infection than CRP. Produced by thyroid C cells and neuroendocrine cells in response to bacterial endotoxins. Remains low in viral infections and autoimmune inflammation. Useful in guiding antibiotic therapy (de-escalation when PCT falling) |
| Blood cultures (at least 2 sets from different sites before antibiotics) | Gold standard for identifying bacteraemia. Each set = 1 aerobic + 1 anaerobic bottle. Timing: ideally during a spike/rigor (highest bacterial load). Sensitivity ~70–80% for true bacteraemia |
| Urinalysis + urine C/ST | Screen for UTI — dipstick (nitrites = Gram-neg bacteria; leukocyte esterase = pyuria) + microscopy + culture |
| CXR | Pneumonia, TB, lung abscess, pleural effusion, mediastinal lymphadenopathy |
| LFTs | Hepatitis, cholangitis, liver abscess; cholestatic pattern (↑ALP, ↑GGT) vs hepatocellular (↑ALT, ↑AST) |
| Renal function + electrolytes | Assess for AKI (sepsis), guide fluid management |
| Lactate | Marker of tissue hypoperfusion. Lactate > 2 mmol/L in the context of sepsis = septic shock criterion [1][14] |
| Coagulation screen | DIC screening if sepsis suspected (↑PT, ↑aPTT, ↓fibrinogen, ↑D-dimer, ↓platelets) |
| Specific tests based on clinical suspicion | Thick/thin film (malaria), HIV serology, Monospot/EBV serology, hepatitis panel, TB workup (AFB smear, IGRA, sputum culture), autoimmune panel (ANA, dsDNA, RF, ANCA), CT abdomen (abscess), echocardiography (IE), lumbar puncture (meningitis), bone marrow biopsy (haematological malignancy), PET-CT (FUO workup) |
Specific Fever Syndromes — Key HK-Relevant Entities
The modern understanding is critical [1][14]:
- Sepsis: Life-threatening organ dysfunction caused by a dysregulated host response to infection. Identified clinically by an acute change in SOFA score ≥ 2 points due to infection [14]
- Septic shock: A subset of sepsis with circulatory and cellular/metabolic dysfunction associated with higher mortality. Clinically identified by: vasopressor requirement to maintain MAP ≥ 65 mmHg AND serum lactate > 2 mmol/L despite adequate fluid resuscitation [1][14]
qSOFA (quick SOFA) for out-of-ICU screening [14]:
- RR ≥ 22/min
- sBP ≤ 100 mmHg
- Altered GCS (< 15)
- qSOFA ≥ 2 → mortality ≥ 10%; prompts further workup for organ dysfunction
SIRS is No Longer Used for Sepsis Definition
The term SIRS is NO LONGER used since the 2016 Sepsis-3 definition. SIRS criteria (Temperature + HR + RR + WBC) are present in many hospitalized patients who do not develop infection and its ability to predict death is poor compared to SOFA score [1]. However, SIRS criteria are still used for non-infectious conditions (e.g. pancreatitis, burns) and you should still know them:
- Temperature > 38°C or < 36°C
- HR > 90 bpm
- RR > 20/min or PaCO₂ < 32 mmHg
- WBC > 12,000/mm³ or < 4,000/mm³ or > 10% immature bands [1]
Progressive organ dysfunction in an acutely ill patient such that homeostasis cannot be maintained without intervention [1]
| System | Pathology |
|---|---|
| Respiratory | ARDS |
| Cardiovascular | Septic shock |
| Hepatic | Jaundice / GI bleeding / Paralytic ileus |
| Renal | Acute tubular necrosis / AKI |
| Neurological | Septic encephalopathy / Critical illness polyneuropathy |
| Haematological | DIC |
Definition: ANC ≤ 0.5 × 10⁹/L (or ≤ 1 × 10⁹/L with predicted decline to ≤ 0.5 in 24–48h) + pyrexia > 38.3°C or > 38°C for > 1 hour [2]
- Occurs in 10–50% of solid tumours but risk is much higher in haematological malignancies
- The blunted inflammatory response means classical signs of infection may be absent — no pus, no infiltrate on CXR, no localizing signs
- This is a medical emergency requiring empirical broad-spectrum antibiotics within 60 minutes of presentation
High Yield Summary
Definition: Fever = ↑hypothalamic set-point via PGE₂ → body actively heats (chills/rigors). Hyperthermia = set-point normal but heat gain > loss (antipyretics don't work).
Threshold: > 38°C (clinical); > 38.3°C (FUO, neutropenic fever). Hypothermia (< 36°C) can indicate severe sepsis.
Pyrogenic pathway: PAMPs/DAMPs → TLRs on macrophages → IL-1/IL-6/TNF-α → OVLT → COX-2 → PGE₂ → EP3 receptors → ↑set-point → vasoconstriction + shivering = fever + chills.
Post-op fever (5 W's): Wind (atelectasis, day 0-2), Water (UTI/anastomotic leak, day 3-5), Wound (SSI, day 5-7), Walking (DVT/PE, day 5+), Wonder drugs (drug fever, day 7-10). Also: Withdrawal, Wonky glands.
Sepsis-3 (2016): Sepsis = infection + SOFA ≥ 2. Septic shock = vasopressor for MAP ≥ 65 + lactate > 2. qSOFA: RR ≥ 22, sBP ≤ 100, altered GCS. SIRS criteria no longer define sepsis.
FUO: ≥ 38.3°C for ≥ 3 weeks, no diagnosis after appropriate workup. ~20% remain unknown.
HK-specific: TB (high prevalence), Klebsiella liver abscess (DM), dengue, S. suis (raw pork).
Key exam approach: History (travel, sexual, occupation, drugs, exposures, animal contact). Exam: skin, eyes, teeth, heart (murmur), lungs, abdomen (liver/spleen), LN, rectal/pelvic. Ix: CBC, CRP, ESR, blood culture, urine MC, CXR, LFT, RFT, lactate.
Relative bradycardia: Typhoid, Legionella, drug fever, lymphoma, factitious fever.
Rigors point toward bacteraemia, Gram-negative sepsis, cholangitis, malaria, abscess.
Active Recall - Fever/Chills
[1] Senior notes: felixlai.md (Sepsis and SIRS section, pp. 34–36) [2] Senior notes: Ryan Ho Haemtology.pdf (Neutropenic Fever, p. 70) [3] Lecture slides: murtagh merge.pdf (Fever that is prolonged, p. 53) [4] Senior notes: maxim.md (Liver abscess section, p. 258) [5] Senior notes: Ryan Ho Respiratory.pdf (Pneumonia, p. 61) [6] Senior notes: Ryan Ho Urogenital.pdf (UTI, pp. 122, 128) [7] Senior notes: Ryan Ho GI.pdf (Liver Abscess, pp. 237–239) [8] Senior notes: Ryan Ho Neurology.pdf (Meningitis, p. 142) [9] Senior notes: Ryan Ho Cardiology.pdf (Myocarditis, p. 165) [10] Senior notes: Ryan Ho Rheumatology.pdf (SSTIs, p. 135) [11] Senior notes: Ryan Ho Rheumatology.pdf (Septic arthritis, p. 67) [12] Senior notes: maxim.md (Post-op fever, pp. 61, 64) [13] Senior notes: felixlai.md (Acute cholangitis, p. 745); Ryan Ho GI.pdf (RUQ pain, p. 209) [14] Senior notes: Ryan Ho Critical Care.pdf (Septic Shock, pp. 22, 15) [15] Senior notes: Ryan Ho Opthalmology.pdf (Endophthalmitis, p. 32) [16] Senior notes: Ryan Ho Endocrine.pdf (Subacute thyroiditis, p. 31)
Differential Diagnosis of Fever/Chills
Before diving into a list, let's understand how to think about differential diagnosis for fever. Fever is a symptom, not a disease. It is the body's universal alarm signal — the final common pathway of PGE₂-mediated hypothalamic set-point elevation, triggered by almost any process that releases endogenous pyrogens (IL-1, IL-6, TNF-α). This means the differential is enormous and you need a systematic framework to narrow it down.
The approach hinges on three questions asked in sequence:
- What is the clinical context? (Community-acquired vs hospital-acquired vs post-operative vs immunocompromised vs returned traveller vs paediatric)
- What is the duration? (Acute < 7 days → mostly self-limiting viral or acute bacterial; Subacute 1–3 weeks → abscess, TB, IE; Chronic > 3 weeks → FUO framework)
- What are the localizing clues? (History, examination and basic investigations narrow the enormous list to a handful of possibilities)
"Prolonged fever is usually an uncommon presentation of a common disorder (unless recent travel, especially to the tropics)" [3]
"Fever in the elderly is sepsis until proved otherwise (especially lungs and urinary tract)" [3]
Murtagh's Diagnostic Strategy for Prolonged Fever
This is the high-yield lecture framework and should be your default structure in exams [3]:
| Diagnosis | Why It's Common | Key Discriminating Feature |
|---|---|---|
| Pyogenic abscess (anywhere, e.g. liver, pelvis) [3] | Abscesses are walled-off pockets of infection that the immune system cannot fully clear → persistent antigenic stimulation → continuous cytokine/pyrogen release → spiking/swinging fever with chills and rigors [4] | Swinging fever pattern, localizing pain (RUQ for liver abscess, pelvic pain for pelvic abscess), ↑CRP/WCC, tender hepatomegaly for liver abscess. CT shows rim-enhancing collection |
| Pneumonia (viral, bacterial, atypical) [3] | Lungs have enormous surface area constantly exposed to inhaled pathogens; alveolar macrophages activate → cytokine cascade → fever. Accounts for 17.6% of deaths in HK [5] | Cough, sputum, pleuritic chest pain, dyspnoea; crackles/bronchial breathing on auscultation; consolidation on CXR |
| Epstein–Barr mononucleosis [3] | EBV infects B-lymphocytes via CD21 → massive CD8+ T-cell response → cytokine storm → prolonged fever (can last 2–4 weeks). Very common in young adults. | Triad of fever + tonsillar pharyngitis + lymphadenopathy (posterior cervical) [17]; splenomegaly (50–60%); atypical lymphocytosis on PBS; morbilliform rash after ampicillin |
| Viral upper respiratory tract infection [3] | The most common communicable disease worldwide; innate immune response to viral replication → interferon and cytokine release → fever (usually low-grade, self-limiting < 7 days) [18] | Rhinorrhoea, sneezing, sore throat, malaise; no consolidation on CXR; WCC normal or ↓ |
| Urinary infection (including chronic pyelonephritis) [3] | Ascending infection from urethra → bladder → kidney. Most common cause of fever in the elderly [6], often with atypical/non-specific presentation. | Dysuria, frequency, urgency (cystitis); loin pain, fever with rigors, Murphy's kidney punch tenderness (pyelonephritis) [19]; positive urine dipstick (nitrites, leukocyte esterase) |
These are the "must-not-miss" diagnoses — either because they are life-threatening if delayed or because they have a narrow treatment window.
Vascular:
| Diagnosis | Key Features |
|---|---|
| Vasculitides (polyarteritis nodosa, giant cell arteritis/polymyalgia rheumatica) [3] | PAN: systemic necrotizing vasculitis of medium arteries → fever, weight loss, tender subcutaneous nodules, mononeuritis multiplex, renal insufficiency [20]. GCA/PMR: elderly > 50y, new-onset temporal headache, jaw claudication, ↑↑ESR (often > 100), risk of permanent visual loss from anterior ischaemic optic neuropathy → start steroids immediately if suspected |
Infection:
| Diagnosis | Key Features & Why It Matters |
|---|---|
| HIV/AIDS [3] | Acute seroconversion illness (2–6 weeks post-exposure): fever, pharyngitis, rash, lymphadenopathy, myalgia — mimics EBV. Advanced HIV: opportunistic infections (PCP, CMV, MAC, Cryptococcus, Toxoplasma) cause persistent fever |
| Malaria and other tropical diseases [3] | P. falciparum = medical emergency. Cyclical fevers (tertian/quartan) with rigors. Travel to endemic area within 1 year. Thick/thin blood film is diagnostic |
| Zoonoses (e.g. leptospirosis, Q fever, listeriosis) [3] | Leptospirosis: rat urine exposure, biphasic fever + conjunctival suffusion + myalgia + jaundice + AKI (Weil's disease). Q fever: Coxiella burnetii, farm animal contact → atypical pneumonia, hepatitis, culture-negative endocarditis [9] |
| Typhoid/paratyphoid fever [3] | Salmonella typhi/paratyphi: faecal-oral transmission, travel to South Asia. Step-ladder fever (first week), relative bradycardia, rose spots, hepatosplenomegaly. Blood culture (1st week) or stool culture (2nd week) |
| Tuberculosis [3] | TB should be considered in ALL cases of pyrexia of unknown origin [21]. HK prevalence ~60/100k. Pulmonary TB: chronic cough, haemoptysis, night sweats, weight loss, upper lobe cavitary lesion. Extrapulmonary: TB meningitis (insidious onset, CN palsies, CSF lymphocytic pleocytosis, ↓glucose, ↑↑protein) [8], miliary TB (diffuse micronodular CXR pattern) [21], cryptic TB in elderly |
| Osteomyelitis [3] | Haematogenous (children, vertebral bodies) or contiguous spread (diabetic foot). Persistent fever + localized bony pain + ↑ESR/CRP. MRI is gold standard imaging |
| Chronic septicaemia/bacteraemia [3] | Persistent or intermittent bacteraemia from uncontrolled focus: abscess, infected prosthetic material, endovascular graft infection |
| Infective endocarditis [3] | Persistent fever in susceptible individuals (prosthetic valves, structural heart disease, IVDU) [9]. Changing murmurs, Osler nodes, Janeway lesions, splinter haemorrhages, embolic phenomena (stroke, renal infarcts). Blood culture + echocardiography are key investigations. Diagnosed by Modified Duke Criteria [9] |
| Lyme disease [3] | Borrelia burgdorferi from tick bite. Erythema migrans (target lesion) → disseminated (CN VII palsy, carditis, polyarthritis) → late (chronic arthritis, encephalopathy). Rare in HK but consider in travellers from endemic areas |
| Syphilis (secondary) [3] | Treponema pallidum. Secondary syphilis: widespread maculopapular rash (including palms/soles — classic!), condylomata lata, mucous patches, fever, lymphadenopathy, 4–10 weeks after primary chancre. Serology: VDRL/RPR screen → confirm with FTA-ABS/TPHA |
Cancer:
| Diagnosis | Key Features |
|---|---|
| Lymphoma and leukaemia [3] | Lymphoma: B symptoms (fever, night sweats, > 10% weight loss in 6 months), painless lymphadenopathy, hepatosplenomegaly. Leukaemia: marrow failure (anaemia, neutropenic infections, bleeding) + organ infiltration [22]. Fever in leukaemia is usually due to infection (especially in neutropenic fever) rather than tumour fever [22] |
| Solid cancers (e.g. lung, kidney) [3] | Renal cell carcinoma: classic "internist's tumour" with paraneoplastic fever, polycythaemia, hypercalcaemia. HCC: consider in HK given high HBV prevalence. Tumour fever from cytokine release (IL-6, TNF-α) |
| Disseminated [malignancy] [3] | Widespread metastatic disease → tissue necrosis → DAMP release → cytokine-mediated fever |
Other:
| Diagnosis | Key Features |
|---|---|
| Inflammatory bowel disease (e.g. Crohn's disease) [3] | Crohn's: fever + abdominal pain + diarrhoea (often bloody) + weight loss. Extra-intestinal manifestations (erythema nodosum, pyoderma gangrenosum, uveitis, arthritis). Can form intra-abdominal abscesses/fistulae → secondary fever |
These are the diagnoses that clinicians frequently overlook — high yield for exams because they test your breadth of thinking [3]:
| Diagnosis | Why It's Missed | Key Clues |
|---|---|---|
| Connective tissue disorder (e.g. rheumatoid arthritis, systemic lupus erythematosus) [3] | Fever may precede the classic joint/skin manifestations by weeks. SLE can present as isolated fever (especially in young women). Adult-onset Still's disease: quotidian spiking fever + evanescent salmon rash + arthralgia + sore throat + ferritin ↑↑↑ | ANA, dsDNA, complement levels; ferritin for Still's |
| Sarcoidosis [3] | Granulomatous inflammation → cytokine release → low-grade fever. Non-caseating granulomas can affect any organ. | Bilateral hilar lymphadenopathy on CXR, ↑ACE, erythema nodosum, uveitis, hypercalcaemia |
| Drug idiosyncrasies [3] | Patient appears "paradoxically well" for degree of fever. Type IV hypersensitivity → onset 7–10 days after starting drug. Common culprits: antibiotics, anticonvulsants, allopurinol | Temporal relationship to drug initiation; resolves within 48–72h of drug cessation; peripheral eosinophilia in some cases |
| Diagnosis | Key Features |
|---|---|
| Factitious fever [3] | Self-induced or fabricated; suspect in young healthcare workers with atypical fever patterns, no objective cause, temperature discrepancies between sites (e.g. rectal vs tympanic). Pulse-temperature dissociation (no tachycardia despite "high fever"). No diaphoresis during defervescence |
The 20% Rule
Up to 20% of FUO cases remain unknown even after extensive workup [3]. This is important to remember — not every fever will yield a diagnosis, and many of these patients have a benign course with spontaneous resolution.
The following diagram shows how to narrow the differential based on localizing features from history and examination:
Differential Diagnosis by Clinical Setting
Already covered in the prior section — the 5/7 W's framework [12]. Key point: the timing narrows the differential.
| Days Post-Op | Most Likely | Second-Line Considerations |
|---|---|---|
| 0–2 | Wind (atelectasis) | Malignant hyperthermia, transfusion reaction, pre-existing infection |
| 3–5 | Water (UTI), Anastomotic leak | Pneumonia (aspiration), CLABSI |
| 5–7 | Wound (SSI) | C. diff colitis, acalculous cholecystitis |
| 5+ | Walking (DVT/PE) | — |
| 7–10 | Wonder drugs (drug fever) | — |
| Any | Withdrawal, Wonky glands | Infected central line, acute pancreatitis [12] |
ANC ≤ 0.5 × 10⁹/L + fever > 38.3°C or > 38°C for > 1h [2]
The differential is narrowed by the immunosuppressed state:
- Bacterial (most common): Gram-negative bacilli (E. coli, Klebsiella, Pseudomonas), Gram-positive cocci (S. aureus, coagulase-negative staph from lines, viridans strep)
- Fungal (if prolonged neutropenia > 7 days or refractory fever): Candida spp, Aspergillus spp
- Viral: HSV reactivation, CMV
- No identifiable source in ~30–50% of cases — but empirical antibiotics are still mandatory
Neutropenic Fever Is a Medical Emergency
Classic signs of infection (pus, infiltrate on CXR, localizing signs) may be absent because neutrophils are needed to generate these responses. A low threshold for empirical broad-spectrum antibiotics (within 60 minutes) is critical. Even the perianal area must be examined (but avoid rectal thermometers or DRE in severely neutropenic patients due to mucosal disruption risk).
| Incubation | Diagnoses to Consider |
|---|---|
| Short (< 2 weeks) | Dengue, chikungunya, Zika, influenza, acute HIV, rickettsial disease, leptospirosis, acute hepatitis A/E |
| Medium (2–6 weeks) | Malaria (can present up to 1 year), typhoid/paratyphoid, acute hepatitis B, acute schistosomiasis (Katayama fever), amoebiasis, brucellosis |
| Long (> 6 weeks) | TB, visceral leishmaniasis, amoebic liver abscess (onset usually within 8–20 weeks, 95% within 5 months) [7], chronic hepatitis, HIV |
The three mandatory investigations in a returned traveller with fever: thick and thin blood film for malaria, blood cultures, and dengue serology (if travel to endemic area).
| Scenario | Top Differentials |
|---|---|
| Diabetic patient + spiking fever + RUQ pain | Klebsiella pneumoniae liver abscess — must screen for endophthalmitis and meningitis [4][7][15] |
| Elderly + non-specific ↓GC + fever | UTI, pneumonia, TB (including cryptic/miliary TB) [3][6][21] |
| Raw pork consumption | Streptococcus suis meningitis — classic HK/South China entity [8] |
| IVDU + fever | Right-sided IE (S. aureus) [3][9], skin/soft tissue abscess, hepatitis B/C, septic arthritis |
| Recent antibiotic course + fever + diarrhoea | Clostridioides difficile colitis [12] |
| Young woman + fever + joint pain + rash | SLE, adult-onset Still's disease, viral arthritis, disseminated gonococcal infection |
The lecture slides provide a specific paediatric framework [23]:
Serious disorders not to be missed in the febrile child [23]:
- Acute appendicitis
- Tuberculosis
- Rheumatic fever
- Endocarditis
- Tropical infections e.g. malaria
- Atypical infections e.g. zoonoses
- Henoch-Schönlein purpura (IgA vasculitis — fever + purpuric rash on buttocks/lower limbs + abdominal pain + arthralgia + renal involvement)
- Kawasaki disease (persistent fever) — fever ≥ 5 days + ≥ 4 of: bilateral non-exudative conjunctivitis, oral mucous membrane changes, polymorphous rash, extremity changes (erythema/oedema → desquamation), cervical lymphadenopathy. Risk of coronary artery aneurysms if untreated
- Heatstroke/hot car
- Neuroblastoma/sarcoma [23]
- Masquerades checklist: drugs (e.g. penicillin, antihistamines), UTI [23]
- Is the patient trying to tell me something? → Parental or Munchausen by proxy [23]
Key paediatric history [23]: detailed account from parents — vomiting, diarrhoea, sweating, cough, wheeze, headache, other pain, cognition, photophobia, urinary symptoms. Ask about immunisation (past and recent), infectious contacts, animal contact and travel. Past history: ?splenectomy
Key paediatric examination [23]: appearance, interaction and level of activity, colour, hydration, chest movement, vital signs including peripheral perfusion. Examine skin for rashes, vesicles and purpura. Examine ears and throat. Basic neurological signs, especially neck stiffness and fontanelles
Some differential diagnoses are commonly confused. Here is how to tell them apart, explained from first principles:
| DDx Pair | Key Distinguishing Features |
|---|---|
| Pyogenic vs Amoebic liver abscess | Pyogenic: often polymicrobial, multiple abscesses, blood culture +ve in 50%; Amoebic: single R lobe abscess (90%), anchovy paste aspirate, amoebic serology +ve (92–97% at presentation), travel to endemic area, bloody dysentery in < 1/3 [7]. Both cannot be distinguished by CT [7] |
| Bacterial meningitis vs TB meningitis | Bacterial: acute onset (hours to 1–2 days), CSF shows ↑↑PMNs, ↓glucose, ↑protein; TB: subacute/insidious onset (days to weeks), CSF shows ↑lymphocytes, ↓↓glucose, ↑↑↑protein (can be very high 2–6 g/dL) [8][21], CN palsies, basal meningeal enhancement |
| Pneumonia vs PE | Both can cause fever, pleuritic chest pain, dyspnoea, CXR changes. PE: sudden onset, risk factors for VTE, no consolidation (but Hampton hump or Westermark sign possible), tachycardia out of proportion, D-dimer ↑↑, CTPA diagnostic. Pneumonia: productive cough, consolidation on CXR, ↑WCC with neutrophilia |
| Infective endocarditis vs occult abscess | Both cause persistent fever. IE: changing murmur, embolic phenomena (stroke, Roth spots, Janeway, Osler), +ve blood cultures, vegetation on echo [9]. Abscess: localizing pain/tenderness, swinging fever, CT shows collection |
| Drug fever vs infection | Drug fever: patient "paradoxically well", onset 7–10 days after drug, may have relative bradycardia, peripheral eosinophilia, resolves 48–72h after drug cessation. Infection: source usually identifiable, localizing signs, WCC/CRP usually ↑↑ |
| Lymphoma vs infection | Both can present with fever, night sweats, weight loss, lymphadenopathy. Lymphoma: painless, rubbery, non-tender LNs; alcohol-induced LN pain (rare but pathognomonic for Hodgkin); LN biopsy diagnostic. Infection: tender LNs, ↑WCC, positive cultures |
| Category | Diagnoses |
|---|---|
| Probability diagnoses | Pyogenic abscess, pneumonia, EBV mononucleosis, viral URTI, urinary infection [3] |
| Vascular | Vasculitides (PAN, GCA/PMR) [3] |
| Infection | HIV/AIDS, malaria/tropical diseases, zoonoses (leptospirosis, Q fever, listeriosis), typhoid/paratyphoid, TB, osteomyelitis, chronic septicaemia, IE, Lyme disease, secondary syphilis [3] |
| Cancer | Lymphoma/leukaemia, solid cancers (lung, kidney), disseminated malignancy [3] |
| Other | IBD (Crohn's) [3] |
| Pitfalls (often missed) | CTD (RA, SLE), sarcoidosis, drug idiosyncrasies [3] |
| Rarities | Factitious fever [3] |
| Unknown | Up to 20% of FUO [3] |
High Yield Summary — Differential Diagnosis of Fever/Chills
Default framework: Murtagh's strategy — probability diagnoses first (abscess, pneumonia, EBV, URTI, UTI), then serious-not-to-miss (infections: HIV, malaria, TB, IE, typhoid; cancers: lymphoma, leukaemia, RCC; vascular: vasculitides), then pitfalls (CTD, sarcoidosis, drug fever), then rarities (factitious fever).
Localizing approach: Respiratory → pneumonia/TB; Urinary → UTI/pyelonephritis; Abdominal → cholangitis/liver abscess; CNS → meningitis/encephalitis; Cardiac → IE/myocarditis; MSK → septic arthritis/osteomyelitis; Skin → cellulitis/SSI.
No localizing features: Use duration — acute (viral), subacute (abscess/IE/TB/typhoid), chronic (FUO framework).
HK-specific: TB (all unexplained fever!), Klebsiella liver abscess (DM), S. suis meningitis (raw pork), dengue, high HBV prevalence (HCC).
Post-op: 5 W's by timing. Neutropenic fever: medical emergency, 60-min door-to-antibiotic.
Paediatric "must-not-miss": Kawasaki disease (persistent fever > 5 days), rheumatic fever, meningitis, appendicitis, HSP.
Up to 20% of FUO remains unknown — this is a normal outcome, not a clinical failure.
Active Recall - Differential Diagnosis of Fever/Chills
References
[2] Senior notes: Ryan Ho Haemtology.pdf (Neutropenic Fever, p. 70) [3] Lecture slides: murtagh merge.pdf (Fever that is prolonged, pp. 52–53) [4] Senior notes: maxim.md (Liver abscess section, p. 258) [5] Senior notes: Ryan Ho Respiratory.pdf (Pneumonia, p. 61) [6] Senior notes: Ryan Ho Urogenital.pdf (UTI in elderly, p. 128) [7] Senior notes: Ryan Ho GI.pdf (Liver Abscess — Pyogenic p. 237, Amoebic p. 239) [8] Senior notes: Ryan Ho Neurology.pdf (Meningitis, pp. 142, 144) [9] Senior notes: Ryan Ho Cardiology.pdf (Infective Endocarditis, pp. 148–149) [12] Senior notes: maxim.md (Post-op fever, pp. 61, 64) [15] Senior notes: Ryan Ho Opthalmology.pdf (Endophthalmitis, p. 32) [17] Senior notes: Ryan Ho Respiratory.pdf (Infectious mononucleosis, p. 53) [18] Senior notes: Ryan Ho Respiratory.pdf (URTI, p. 48) [19] Senior notes: Ryan Ho Urogenital.pdf (Acute Pyelonephritis, p. 127) [20] Senior notes: Ryan Ho Rheumatology.pdf (PAN, p. 159) [21] Senior notes: Ryan Ho Respiratory.pdf (TB — cryptic/miliary, pp. 79, 81) [22] Senior notes: Ryan Ho Haemtology.pdf (Acute Leukaemia, p. 51) [23] Lecture slides: murtagh merge.pdf (The febrile child, p. 94)
Diagnostic Criteria, Algorithm and Investigation Modalities for Fever/Chills
Here's the crucial distinction: fever itself is not a diagnosis — it is a sign. You don't diagnose "fever"; you diagnose the cause of the fever. Therefore, the diagnostic workup for fever/chills is fundamentally a source-seeking exercise. The investigations you choose are driven by the clinical context and localizing clues, not by the fever itself.
That said, certain specific fever syndromes do have formal diagnostic criteria (sepsis, FUO, neutropenic fever, and specific causes like IE, cholangitis, etc.), and understanding these is essential.
Formal Diagnostic Criteria for Key Fever Syndromes
These criteria identify when fever has crossed the line from "body fighting infection" into "body destroying itself through dysregulated immune response" [14]:
| Term | Criteria | Rationale |
|---|---|---|
| Sepsis | Suspected/documented infection + acute change in SOFA score ≥ 2 [14] | SOFA assesses 6 organ systems (respiratory, coagulation, liver, cardiovascular, CNS, renal). A rise ≥ 2 indicates new organ dysfunction attributable to infection |
| Septic shock | Sepsis + vasopressor requirement for MAP ≥ 65 mmHg + serum lactate > 2 mmol/L despite adequate fluid resuscitation [14] | Lactate > 2 reflects cellular hypoxia from inadequate O₂ delivery; vasopressor need reflects persistent vasodilation despite volume |
| qSOFA (screening) | ≥ 2 of: RR ≥ 22/min, sBP ≤ 100 mmHg, altered GCS < 15 [14] | Quick bedside tool for out-of-ICU patients; qSOFA ≥ 2 → mortality ≥ 10%, prompts SOFA assessment |
SOFA Score components (each scored 0–4, total 0–24):
| System | Parameter | 0 | 1 | 2 | 3 | 4 |
|---|---|---|---|---|---|---|
| Respiratory | PaO₂/FiO₂ | ≥ 400 | < 400 | < 300 | < 200 with vent | < 100 with vent |
| Coagulation | Platelets (×10⁹/L) | ≥ 150 | < 150 | < 100 | < 50 | < 20 |
| Liver | Bilirubin (µmol/L) | < 20 | 20–32 | 33–101 | 102–204 | > 204 |
| Cardiovascular | MAP or vasopressors | MAP ≥ 70 | MAP < 70 | Dopa ≤ 5 or dobutamine | Dopa > 5 or epi ≤ 0.1 or norepi ≤ 0.1 | Dopa > 15 or epi > 0.1 or norepi > 0.1 |
| CNS | GCS | 15 | 13–14 | 10–12 | 6–9 | < 6 |
| Renal | Creatinine (µmol/L) or UO | < 110 | 110–170 | 171–299 | 300–440 or UO < 500mL/d | > 440 or UO < 200mL/d |
SIRS vs Sepsis-3
SIRS criteria are NO LONGER used to define sepsis (since 2016) because SIRS criteria are present in many hospitalized patients who do not develop infection and their ability to predict death is poor compared to SOFA [1]. However, SIRS is still used for non-infectious systemic inflammation (pancreatitis, burns). The old SIRS criteria:
- Temperature > 38°C or < 36°C
- HR > 90 bpm
- RR > 20/min or PaCO₂ < 32 mmHg
- WBC > 12,000 or < 4,000 or > 10% bands [1]
Classic Petersdorf & Beeson definition (modified) [3]:
- Fever ≥ 38.3°C
- Duration ≥ 3 weeks
- No diagnosis after appropriate investigation (including at least 3 outpatient visits or 3 days in hospital)
Why these specific thresholds? The 38.3°C cutoff excludes low-grade habitual hyperthermia and physiological variation. The 3-week duration ensures self-limiting viral illnesses have resolved. The investigation requirement prevents premature labelling.
Up to 20% remain unknown [3].
ANC ≤ 0.5 × 10⁹/L (or ≤ 1.0 × 10⁹/L with predicted decline to ≤ 0.5 within 24–48h) + pyrexia > 38.3°C or > 38.0°C sustained for > 1 hour [2]
Why this matters: neutrophils are your main defence against bacteria and fungi. Below 0.5 × 10⁹/L, the risk of life-threatening infection is very high, and classical signs (pus, consolidation, erythema) may be absent because neutrophils are needed to generate these responses.
These come into play once clinical features point toward a specific source:
a. Infective Endocarditis — Modified Duke Criteria [9]
| Category | Criteria |
|---|---|
| Pathological (definite) | Micro-organisms demonstrated in a vegetation OR IE confirmed by histology |
| Clinical — Definite IE | 2 major OR 1 major + 3 minor OR 5 minor |
| Clinical — Possible IE | 1 major + 1 minor OR 3 minor |
Major criteria:
- Positive blood culture: typical organisms in 2 separate cultures or > 12h apart (S. aureus, viridans strep, S. bovis, HACEK, community-acquired enterococci without primary focus) OR organisms more commonly skin contaminants in 3 or majority of ≥ 4 separate cultures (1st and last drawn ≥ 1h apart) OR single positive culture or phase I IgG titre > 1:800 for Coxiella burnetii [9]
- Evidence of endocardial involvement: vegetation, abscess, or prosthetic valve dehiscence on echo OR new valvular regurgitation (change in pre-existing murmur not sufficient) [9]
Minor criteria (mnemonic: Bacterial Endocarditis FIVE PM [9]):
- Bacteria isolated (suggestive but not meeting major criterion)
- Endocardial involvement — not applicable as minor (covered in major)
- Fever ≥ 38.0°C
- Immunological phenomena: GN, Osler nodes, Roth spots, ↑RF
- Vascular phenomena: embolism, septic PE, mycotic aneurysm, Janeway lesion, conjunctival haemorrhage
- Predisposition: VHD/cardiac conditions or IVDU
- Microbiological evidence (minor level)
b. Acute Cholangitis — Tokyo Guidelines 2018 (TG18) [13][24]
Suspected diagnosis = ONE of (fever/shaking chills OR lab evidence of inflammation: abnormal WBC/↑CRP) AND ONE of (jaundice OR abnormal liver chemistries: ↑AST/ALT/ALP/GGT) [13]
Definite diagnosis = Suspected criteria met PLUS BOTH biliary dilation on imaging AND evidence of aetiology (stone, stricture, stent) [13]
c. Acute Cholecystitis — Tokyo Guidelines 2013 (TG13) [24][25]
| Component | Criteria |
|---|---|
| A: Local signs | Murphy's sign (Sens 50–65%, Spec 79–96%) OR RUQ mass/pain/tenderness |
| B: Systemic signs | Fever OR ↑CRP > 3 mg/dL OR ↑WBC |
| C: Imaging | Findings characteristic of acute cholecystitis (thick wall > 3mm, distended GB, pericholecystic fluid) |
| Suspected | 1× A + 1× B |
| Definite | 1× A + 1× B + 1× C [24] |
d. Acute Pancreatitis — Revised Atlanta Classification 2013 [26]
Diagnosis requires ≥ 2 of 3:
- Acute onset of persistent, severe epigastric pain often radiating to the back (Clinical)
- Serum amylase or lipase ≥ 3× upper limit of normal (Biochemical)
- Characteristic imaging findings on USG, CT or MRI (Radiological) [26]
The following algorithm represents the clinical reasoning pathway from "patient with fever" to "specific diagnosis":
Investigation Modalities — Detailed Interpretation
These should be ordered for every patient with significant fever. The basics are: FBE, ESR/CRP, CXR and sinus films, urine MC, routine blood chemistry, LFTs, blood culture. [3]
| Investigation | What It Measures | Key Findings in Fever | Interpretation from First Principles |
|---|---|---|---|
| FBE / CBC with differential [3] | Cell counts + WBC subtypes | Leukocytosis with neutrophilia: bacterial infection. Left shift (↑bands/metamyelocytes): marrow mobilizing immature neutrophils under stress — indicates severe infection/sepsis [27]. Leukopenia: overwhelming sepsis (marrow exhaustion), viral, typhoid. Lymphocytosis: viral, TB, lymphoma. Atypical lymphocytes: EBV (prototypical), other viral infections — these are activated CD8+ T cells, NOT neoplastic [27]. Eosinophilia: parasites, drug reaction, vasculitis. Pancytopenia: marrow infiltration, overwhelming sepsis, aplastic crisis | The differential count tells you which arm of the immune system is responding: neutrophils → bacterial; lymphocytes → viral/chronic; eosinophils → parasitic/allergic |
| Peripheral blood smear (PBS) [27] | Morphology | Left shift: band forms, metamyelocytes → severe infection. Leukoerythroblastic picture: left shift + nucleated RBCs ± tear drop cells → marrow infiltration [27]. Blasts ≥ 20%: diagnostic of acute leukaemia [22]. Auer rods: confirm myeloblasts (AML). Schistocytes: microangiopathic haemolysis (DIC, TTP-HUS). Smudge cells: CLL. Malaria parasites: thick film for detection, thin film for speciation | PBS is the single most information-dense haematological investigation — always correlate with clinical picture |
| ESR [3] | Rate of RBC sedimentation (mm/h) | ↑ in inflammation (slow to rise, slow to fall). Very ↑ ESR (> 100): myeloma, TB, abscess, lymphoma, GCA, autoimmune disease | ESR rises because acute phase proteins (fibrinogen, immunoglobulins) coat RBCs → ↑rouleaux → faster settling. It is non-specific but very high values narrow the differential |
| CRP [3] | Hepatic acute phase protein (mg/L) | Rises within 6–8h, peaks at 48h. > 100 mg/L: strongly suggests bacterial rather than viral infection. Very useful for monitoring treatment response (falls rapidly with effective therapy, half-life ~19h) | CRP is produced by hepatocytes in response to IL-6. It opsonizes pathogens and activates complement. More dynamic than ESR — better for acute monitoring |
| Blood cultures [3] | Identify bacteraemia/fungaemia | Gold standard for bloodstream infection. At least 2 sets from different sites, before antibiotics [9]. Each set = 1 aerobic + 1 anaerobic bottle. For IE: 3 venous cultures at different sites, separated by ≥ 0.5h [9]; +3 more if initially negative. Sensitivity ~70–80% for true bacteraemia | Timing: ideally during spike/rigor (highest bacterial load in bloodstream). Why 2 sites? To distinguish true bacteraemia from contamination. If same organism in 2/2 sets → true; if only 1/2 → likely contaminant (especially CoNS, diphtheroids) |
| Urine MC&S [3] | Pyuria, bacteriuria, culture | Dipstick: nitrites (Gram-neg bacteria reduce urinary nitrates → nitrites; Gram-pos do NOT produce nitrites → can be false-neg), leukocyte esterase (enzyme from WBCs → surrogate for pyuria). Microscopy: WBC > 10/mm³ = pyuria. Culture: ≥ 10⁵ CFU/mL (women), ≥ 10³ CFU/mL (men or catheterized)** [19] | UTI is the most common cause of fever in the elderly [3][6]. A negative dipstick does not exclude UTI in the immunocompromised (may not mount pyuria) |
| CXR [3] | Lung parenchyma, mediastinum, pleura | Consolidation (air bronchograms): lobar pneumonia. Patchy infiltrates: bronchopneumonia. Upper lobe cavitary lesion: TB, lung abscess. Bilateral hilar lymphadenopathy: sarcoidosis, lymphoma. Micronodular pattern: miliary TB [21]. Right basal collapse/effusion: liver abscess complication [7]. Multiple cavitating lesions: septic PE (right-sided IE) [9]. Widened mediastinum: aortic pathology | CXR should be done on every patient with fever and respiratory symptoms. Even without respiratory symptoms, CXR picks up unsuspected pathology ~10% of the time in unexplained fever |
| LFTs [3] | Hepatocellular and biliary markers | Cholestatic pattern (↑ALP, ↑GGT, ↑conjugated bilirubin): biliary obstruction → cholangitis, liver abscess [13]. Hepatocellular pattern (↑ALT, ↑AST): hepatitis (viral, drug, autoimmune). Hypoalbuminaemia: negative acute phase reactant + chronic illness [7]. ↑bilirubin + ↑GGT should raise suspicion of CBD obstruction [25] | The pattern of LFT derangement tells you where in the hepatobiliary system the problem is: hepatocyte damage → transaminases; duct obstruction → ALP/GGT/bilirubin |
| RFT + electrolytes [3] | Renal function, electrolytes | ↑Urea/Cr: dehydration (pre-renal), sepsis-induced AKI (ATN), obstructive uropathy. HypoNa: SIADH (meningitis, pneumonia, malignancy), Addisonian crisis, dilutional. HyperK: AKI, Addisonian crisis, rhabdomyolysis | Monitor for sepsis-related organ dysfunction (renal component of SOFA score) |
| Lactate | Tissue perfusion marker | > 2 mmol/L: indicates tissue hypoperfusion — septic shock criterion when combined with vasopressor need [14]. > 4 mmol/L: severe tissue hypoxia, associated with high mortality | Lactate is produced when cells switch from aerobic to anaerobic metabolism due to inadequate O₂ delivery. In sepsis, this is multifactorial: ↓perfusion + mitochondrial dysfunction + ↑glycolysis from catecholamine surge. Serial lactate clearance is used to guide resuscitation |
Procalcitonin — The Bacterial vs Viral Discriminator
Procalcitonin (PCT) is increasingly used in clinical practice. It is produced by thyroid C-cells and neuroendocrine cells throughout the body in response to bacterial endotoxins and pro-inflammatory cytokines. Crucially, IFN-γ (released during viral infections) inhibits PCT production. This means:
- Bacterial infection: PCT rises significantly (> 0.5 ng/mL suggestive, > 2 ng/mL strongly suggestive)
- Viral infection: PCT remains low (< 0.25 ng/mL)
- Clinical utility: Guides antibiotic de-escalation (stop antibiotics when PCT falling by > 80% from peak or < 0.25 ng/mL)
- Limitations: Can be elevated in non-infectious conditions (major surgery, burns, cardiogenic shock, severe trauma), and may be falsely low early in infection (< 6h)
Other tests depend on clinical pointers (e.g. specific organisms, lymph node biopsy, HIV, tuberculosis, connective tissue auto-antibodies) [3]
| Suspected Source | Investigation | Key Findings & Interpretation |
|---|---|---|
| Liver abscess | Blood culture (positive in up to 50%) [7]; USG abdomen (first-line: multiloculated cystic mass, no vascularity, septation, hypoechoic rim) [4][7]; CT abdomen with contrast (double-target sign: rim-enhancing with central hypodensity; cluster sign) [4]; Image-guided aspiration for C/ST (anchovy paste-like for amoebic, pus for pyogenic) [4]; Amoebic serology (EIA for Ab: 92–97% positive at presentation, may be negative in first 7 days → repeat at 1 week) [7]; Blood glucose (DM screen); CXR (right basal collapse/effusion) [4][7] | CT CANNOT differentiate between pyogenic and amoebic liver abscess [7]. For Klebsiella: urgent eye consult if symptoms of endophthalmitis, monitor for meningitis, colonoscopy for underlying neoplasm [4] |
| Cholangitis | CBC (leukocytosis with neutrophilia), LFT (↑ALP/GGT — cholestatic pattern, ↑conjugated bilirubin), blood/bile culture (with sensitivity testing), USG HBS (dilated CBD > 6mm, ± stone), MRCP/ERCP if obstruction suspected [13] | Diagnosis: TG18 criteria (see above). Positive bile cultures are common with bile duct stones even without clinical cholangitis [13] |
| Cholecystitis | USG HBS (Sens 88%, Spec 80%: gallstones, thick wall > 3mm, distended GB, sonographic Murphy's sign, pericholecystic fluid) [25]; CT abdomen (Sens 94%, Spec 59%: fat stranding not seen on USG) [25]; ± HIDA scan (if USG equivocal: non-filling of GB = obstructed cystic duct, Sens 90–97%) [25] | TG13 criteria for diagnosis [24]. ↑Bilirubin/GGT should raise suspicion of CBD obstruction [25] |
| Pneumonia | CXR (consolidation ± air bronchograms, parapneumonic effusion) [5]; Blood: CBC, RFT (↑urea = severity marker), LFT, ESR/CRP; ± ABG if SaO₂ < 93% [5]; Microbiology: sputum Gram stain and C/ST, blood cultures, urinary Legionella/pneumococcal antigen | Diagnosis based on clinical S/S + compatible CXR findings [5]. Severity assessed by CURB-65 or PSI |
| UTI / Pyelonephritis | Urine dipstick + MC&S; Blood cultures (mandatory in pyelonephritis); USG kidney (mandatory for severe infection to r/o obstruction) [19]; NCCT abdomen if not improving > 72h (r/o renal abscess, obstruction) [19] | Pyelonephritis: classical triad of loin pain + tenderness + fever, Murphy's kidney punch positive [19] |
| Meningitis | CT brain before LP if: altered consciousness, focal signs, papilloedema, seizure, immunocompromised [8]; LP + CSF analysis (see table below); Blood cultures (80% positive in H. influenzae, < 50% in pneumococcus/meningococcus); Blood: CBC, CRP, electrolytes (SIADH), coagulation [8] | Empirical Abx within 6h ± dexamethasone — should NOT be delayed for CT brain [8]. Take blood culture first → give Abx → then LP |
| IE | Blood cultures: 3 venous cultures at different sites, separated by ≥ 0.5h; +3 if initially negative [9]; Echocardiography: TTE as initial screen → TEE if prosthetic valve, TTE non-diagnostic but high suspicion, or TTE positive with risk of complications [9]; Blood: ↑ESR/CRP, NcNc anaemia, leukocytosis; Urine: proteinuria, microscopic haematuria, pyuria, RBC casts; ECG: AV block (paravalvular extension), ischaemia (coronary embolism); CXR: HF, septic pulmonary emboli [9] | Modified Duke Criteria for diagnosis (see above). Mnemonic: Bacterial Endocarditis FIVE PM [9] |
| TB | Sputum AFB smear and culture (3 early morning samples, ± induced sputum), TB-PCR; IGRA (QuantiFERON/T-SPOT); TST (Mantoux); CXR; LP if TBM suspected (CSF: ↓glucose, ↑↑↑protein 2–6 g/dL, lymphocytic pleocytosis) [8][21]; MRI brain (basal meningeal enhancement, hydrocephalus); Tissue biopsy (caseating granuloma) | TB should be considered in ALL cases of pyrexia of unknown origin [21]. Majority of miliary TB are sputum smear-negative (tubercles in interstitium, not airway) → may need BAL or BM aspirate [21] |
| Autoimmune | ANA, anti-dsDNA, complement C3/C4 (SLE); RF, anti-CCP (RA); pANCA, cANCA (vasculitis); ↑↑↑Ferritin > 10,000 (adult-onset Still's disease — characteristically very high); Anti-Ro/La (Sjögren); ESR (↑↑ > 100 in GCA) [28] | Common early features of CTD: unexplained fever, mucocutaneous symptoms, vascular phenomena, polyarthritis, sicca symptoms, serositis. Lab: cytopenia, high ESR, reversed A/G ratio, positive ANA [28] |
| Malignancy | CBC + PBS (blasts → leukaemia); LDH (elevated in lymphoma, metastatic disease — due to high cell turnover); CT TAP (lymphadenopathy, masses, hepatosplenomegaly); PET-CT (metabolically active foci); LN biopsy (architecture, immunohistochemistry); BM aspirate + trephine (if suspected haematological malignancy) [22][27] | Key diagnostic finding for acute leukaemia: > 20% blasts in bone marrow or peripheral blood [22]. MCICM approach for haematological malignancy: Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics [22] |
| Returned traveller | Thick and thin blood film (malaria — thick for detection, thin for speciation); Dengue NS1 antigen (day 1–5) and IgM/IgG serology (day 4+); Typhidot/Widal (typhoid — blood culture in first week, stool culture in second week); Hepatitis panel; HIV serology; Specific serologies based on travel destination | Three mandatory investigations in returned traveller with fever: malaria film, blood cultures, dengue serology (if endemic exposure) |
| Parameter | Normal | Bacterial | Viral | TB | Fungal (Cryptococcal) |
|---|---|---|---|---|---|
| Appearance | Clear | Turbid/purulent | Clear | Clear/fibrin web | Clear |
| Opening pressure | 6–20 cmH₂O | ↑↑↑ | Normal/mild ↑ | ↑↑ | ↑↑ |
| WCC (cells/mm³) | < 5 | ↑↑↑ (100–10,000) | ↑ (10–500) | ↑ (50–500) | ↑ (20–500) |
| Predominant cell | — | Neutrophils | Lymphocytes | Lymphocytes | Lymphocytes |
| Protein (g/L) | 0.15–0.45 | ↑↑ (1–5) | Mild ↑ (0.5–1) | ↑↑↑ (1–6) [8] | ↑ (0.5–3) |
| Glucose (CSF:serum) | > 0.6 | ↓↓ (< 0.4) | Normal (> 0.6) | ↓↓ (< 0.3) | ↓↓ |
| Special | — | Gram stain, C/ST | PCR (HSV, enterovirus) [29] | AFB smear/culture, TB-PCR, ADA | Indian ink, cryptococcal Ag [8] |
Why is glucose low in bacterial and TB meningitis but normal in viral? Bacteria and mycobacteria actively metabolize glucose. The intense neutrophilic/lymphocytic response also consumes glucose via glycolysis. Viruses primarily infect cells without directly consuming CSF glucose, and the inflammatory response is less intense.
Why is protein very high in TB meningitis? The thick basilar exudate characteristic of TBM causes severe disruption of the blood-CSF barrier, allowing massive protein leakage. The chronicity of the inflammation compounds this effect.
When standard investigations fail and fever persists ≥ 3 weeks:
| Investigation | Rationale |
|---|---|
| Repeat the history [3] | Travel, exposures, sexual history, animal contact, medications may not have been volunteered initially. "The history may need to be repeated" [3] |
| PET-CT (¹⁸F-FDG) | The single most useful investigation in FUO workup. FDG accumulates in metabolically active cells (infection, inflammation, malignancy). Identifies occult abscesses, vasculitis (aortitis), lymphoma, sarcoidosis. Diagnostic yield 30–60% in FUO |
| CT chest/abdomen/pelvis | Identify occult abscess, lymphadenopathy, solid tumours, hepatosplenomegaly |
| Echocardiography (TEE) | If any suspicion of IE — TEE > TTE for sensitivity |
| Temporal artery biopsy | If ≥ 50y + new headache + ↑ESR → suspect GCA [30]. Diagnostic criteria for GCA: ≥ 3 of: onset ≥ 50y, new headache, abnormalities of temporal artery, ↑ESR > 50, abnormal biopsy [30]. Must order urgently (< 24–48h) |
| Tissue biopsy | LN biopsy (lymphoma, sarcoid, TB), liver biopsy (granulomatous hepatitis, TB, lymphoma), BM biopsy (haematological malignancy, miliary TB, leishmaniasis) |
| Empirical therapeutic trial | Anti-TB therapy (even without definite evidence, can be life-saving in cryptic TB — 80% mortality if missed) [21]; Steroids if vasculitis/autoimmune strongly suspected; Doxycycline if rickettsial/brucellosis suspected |
PET-CT in FUO — The Game-Changer
PET-CT has revolutionized the FUO workup. By detecting areas of ↑glucose metabolism, it can identify foci of infection (abscesses, osteomyelitis, IE vegetations), inflammation (vasculitis, sarcoidosis), and malignancy (lymphoma, metastases) that are invisible on conventional imaging. Current guidelines recommend PET-CT early in the FUO workup (after basic investigations are negative) rather than as a last resort, because it has a diagnostic yield of 30–60% and can direct subsequent targeted biopsies.
Special Investigation Considerations
First line: FBE/ESR, urinalysis, MCU. Consider: CXR, blood culture, lumbar puncture [23]
Fever is regarded as a temperature > 38°C (rectal or tympanic) [23]. Most fevers in children are caused by viruses and are self-limiting. Distinguish between focal causes (e.g. tonsillitis) and no apparent focus when a more detailed history and examination is required. Be very mindful of septicaemia and endocarditis. [23]
Key differences from adults:
- Lower threshold for LP in febrile infants (especially < 3 months — cannot clinically exclude meningitis)
- Urine collection: clean-catch midstream or catheter specimen (bag specimens have high contamination rate)
- MCU (micturating cystourethrogram) considered if UTI confirmed — to assess for vesicoureteric reflux
The fever pattern itself can narrow the differential when not obscured by antipyretics [27]:
| Pattern | Classic Association | Mechanism |
|---|---|---|
| Continuous | Typhoid, typhus, drug fever, malignant hyperthermia [27] | Sustained antigenic stimulus → continuous pyrogen release |
| Remittent | Non-specific — most bacterial infections [27] | Fluctuating pyrogen levels but never enough clearance to normalize |
| Intermittent | Pyogenic infections, miliary TB, lymphoma [27] | Periodic pyrogen release (e.g. abscess draining then re-accumulating) |
| Relapsing | Malaria (tertian: P. vivax/ovale every 48h; quartan: P. malariae every 72h), Pel-Ebstein fever of Hodgkin lymphoma [27] | Malaria: synchronized erythrocyte lysis releases merozoites + haemozoin → massive pyrogen burst every replication cycle |
High Yield Summary — Diagnostics for Fever/Chills
Sepsis-3: Infection + SOFA ≥ 2 = sepsis. Vasopressor for MAP ≥ 65 + lactate > 2 = septic shock. qSOFA (RR ≥ 22, sBP ≤ 100, altered GCS) for screening.
FUO: ≥ 38.3°C, ≥ 3 weeks, no diagnosis after appropriate workup. ~20% remain unknown. PET-CT is the game-changer investigation.
Neutropenic fever: ANC ≤ 0.5 × 10⁹/L + temp > 38.3°C (or > 38°C for > 1h). Medical emergency — empirical Abx within 60 min.
Basic fever screen (every patient): CBC with diff, ESR/CRP, blood cultures (≥ 2 sets before Abx), urine MC&S, CXR, LFT, RFT, lactate.
IE: Modified Duke Criteria — 2 major, or 1 major + 3 minor, or 5 minor. Blood cultures ×3 from different sites. TEE if prosthetic valve or TTE negative with high suspicion.
Cholangitis: TG18 — (fever/chills OR ↑inflammatory markers) + (jaundice OR abnormal liver chemistries). Definite if + biliary dilation + aetiology on imaging.
CSF interpretation: Bacterial = neutrophils, ↓glucose, ↑protein. Viral = lymphocytes, normal glucose. TB = lymphocytes, very ↓glucose, very ↑↑↑protein. Crypto = lymphocytes, Indian ink +, cryptococcal Ag +.
PBS clues: Left shift = severe infection/sepsis. Atypical lymphocytes = EBV. Blasts ≥ 20% = acute leukaemia. Schistocytes = DIC/TTP.
Key principle: Don't delay empirical antibiotics to complete the workup. Blood cultures BEFORE antibiotics → give antibiotics → then do LP/imaging.
Active Recall - Diagnostic Criteria & Investigations for Fever/Chills
References
[1] Senior notes: felixlai.md (SIRS and sepsis definitions, pp. 34–36) [2] Senior notes: Ryan Ho Haemtology.pdf (Neutropenic Fever, p. 70) [3] Lecture slides: murtagh merge.pdf (Fever that is prolonged, pp. 52–53) [4] Senior notes: maxim.md (Liver abscess, p. 258) [5] Senior notes: Ryan Ho Respiratory.pdf (Pneumonia diagnosis, p. 63) [6] Senior notes: Ryan Ho Urogenital.pdf (UTI in elderly, p. 128) [7] Senior notes: felixlai.md (Liver abscess diagnosis, pp. 437–438); Ryan Ho GI.pdf (Liver abscess, pp. 237, 239) [8] Senior notes: Ryan Ho Neurology.pdf (Meningitis approach and investigations, pp. 142, 145) [9] Senior notes: Ryan Ho Cardiology.pdf (IE approach and Modified Duke Criteria, pp. 149) [13] Senior notes: felixlai.md (Acute cholangitis diagnosis, pp. 521) [14] Senior notes: Ryan Ho Critical Care.pdf (Sepsis-3 and qSOFA, p. 22) [19] Senior notes: Ryan Ho Urogenital.pdf (Acute pyelonephritis, p. 127) [21] Senior notes: Ryan Ho Respiratory.pdf (TB — cryptic/miliary, pp. 79, 81) [22] Senior notes: Ryan Ho Haemtology.pdf (Acute leukaemia, p. 51) [23] Lecture slides: murtagh merge.pdf (The febrile child, p. 95) [24] Senior notes: Ryan Ho GI.pdf (TG13 criteria for acute cholecystitis, p. 248) [25] Senior notes: Ryan Ho GI.pdf (Cholecystitis clinical and imaging, p. 247); felixlai.md (Tokyo criteria, p. 556) [26] Senior notes: felixlai.md (Acute pancreatitis diagnostic criteria, p. 581); Ryan Ho GI.pdf (Revised Atlanta, p. 340) [27] Senior notes: Ryan Ho Fundamentals.pdf (Fever patterns, p. 12; PBS interpretation, p. 390); Ryan Ho Haemtology.pdf (PBS, p. 47) [28] Senior notes: Ryan Ho Rheumatology.pdf (CTD overview, p. 82; Approach to arthritis, p. 29); Ryan Ho Fundamentals.pdf (Arthritis Ix, p. 410) [29] Senior notes: Ryan Ho Neurology.pdf (Encephalitis investigations, p. 149) [30] Senior notes: Ryan Ho Neurology.pdf (GCA diagnostic criteria, p. 65)
Management of Fever/Chills
Before we get into specific therapies, understand the three pillars of managing a febrile patient:
- Resuscitate — Stabilize the patient (ABCDE, fluids, oxygen, vasopressors if shock)
- Find and treat the source — This is the definitive therapy. Antibiotics, drainage, surgery — whatever it takes to eradicate the cause
- Supportive care — Antipyretics, fluids, nutrition, organ support, prevention of complications
The single most important concept: treating the fever itself is secondary to treating the cause. Fever is a symptom, not the enemy. An isolated focus on bringing the temperature down while missing a drainable abscess or an unrecognized sepsis is a catastrophic error.
PILLAR 1: Resuscitation — Management of Sepsis and Septic Shock
This is the most critical management scenario for fever/chills. Delay kills — each hour delay over the first hour of antibiotics leads to 7.6% decrease in survival [14].
All elements should be initiated within the first hour of recognition:
| Element | Detail | Rationale |
|---|---|---|
| 1. Measure lactate | STAT arterial or venous blood gas | Lactate > 2 mmol/L = septic shock criterion [14]. Serial lactate guides resuscitation — aim for lactate clearance ≥ 20% per 2 hours |
| 2. Blood cultures | ≥ 2 sets from different sites, BEFORE antibiotics [9][14] | Identifies organism for targeted therapy. Starting antibiotics first dramatically ↓yield |
| 3. Broad-spectrum IV antibiotics | Within 60 minutes of recognition [14] | Wrong Abx → need for escalation → ↑mortality [14]. Choice depends on suspected source (see below) |
| 4. Rapid IV crystalloid | ≥ 30 mL/kg within first 3 hours if hypotension or lactate ≥ 4 mmol/L [14] | Restores intravascular volume depleted by vasodilation and third-spacing. Crystalloid as initial fluid of choice ± albumin. Do NOT use starch-based colloids → associated with ↑renal failure without survival benefit [14]. Balanced solutions preferred (↓risk of kidney injury vs 0.9% NaCl) [14] |
| 5. Vasopressors | If MAP remains < 65 mmHg after adequate fluid resuscitation | Norepinephrine as 1st choice ± vasopressin or epinephrine [14] |
- Supplemental O₂ should be supplied to all patients — target SpO₂ > 94% [1]
- Intubation and mechanical ventilation may be required for: increased work of breathing that accompanies sepsis, and airway protection since encephalopathy and depressed consciousness frequently complicate sepsis [1]
- CXR and ABG should be obtained following initial stabilization to evaluate for ARDS [1]
| Target | Value | Why |
|---|---|---|
| Urine output | ≥ 0.5 mL/kg/hour | Surrogate for renal perfusion |
| MAP | ≥ 65 mmHg | Minimum for organ perfusion |
| CVP | 8–12 mmHg (if central access) | Static predictor of fluid responsiveness (though dynamic predictors like pulse pressure variation are now preferred) |
| ScvO₂ | ≥ 70% (if central access) | Central venous oxygen saturation — if low, it means tissues are extracting more O₂ than normal → inadequate delivery → need ↑CO or ↑Hb |
Understanding why we choose specific agents requires knowing their receptor pharmacology [1]:
| Drug | Receptors | HR | Contractility | Vasoconstriction | When to Use |
|---|---|---|---|---|---|
| Norepinephrine | α₁ +++ / β₁ ++ | ++ | ++ | +++ | 1st-line vasopressor in septic shock — potent vasoconstrictor with some inotropic effect [14] |
| Vasopressin | V₁ receptor | 0 | 0 | ++ | 2nd-line added to norepinephrine — acts via non-adrenergic pathway, useful when catecholamine resistance develops (sepsis depletes endogenous vasopressin) |
| Epinephrine | α₁ ++ / β₁/β₂ +++ | +++ | +++ | ++ | Alternative to norepinephrine or added when additional inotropic support needed |
| Dobutamine | β₁ +++ | + | +++ | — (not a vasopressor) | Added when cardiac output remains low despite adequate filling pressure — pure inotrope for sepsis-induced myocardial depression [14] |
| Phenylephrine | α₁ +++ | 0 | 0 | +++ | Pure vasoconstrictor — use when tachyarrhythmia limits other agents. Not first-line |
| Dopamine | α/β/dopaminergic | ++ | ++ | ++ | No longer recommended as first-line — higher arrhythmia risk than norepinephrine. "Renal-dose dopamine" is a myth with no proven benefit |
Why norepinephrine first? In septic shock, the dominant haemodynamic problem is vasodilation (↓SVR from NO, vasodilatory prostaglandins, and cytokine-mediated smooth muscle dysfunction). You need a potent vasoconstrictor to restore SVR and MAP. Norepinephrine provides strong α₁ vasoconstriction with enough β₁ effect to maintain cardiac output — the best balance for distributive shock.
| Therapy | Indication | Detail |
|---|---|---|
| Glucocorticoids | Septic shock refractory to fluids and vasopressors | IV hydrocortisone 200 mg/day (50 mg Q6H or continuous infusion). Rationale: sepsis causes relative adrenal insufficiency (↓cortisol response). Steroids restore vascular sensitivity to catecholamines. NOT for all sepsis — only for refractory shock [1] |
| Glucose control | Hyperglycaemia in sepsis | Target blood glucose 7.8–10.0 mmol/L. Stress hyperglycaemia worsens outcomes. Avoid tight control (< 6.1) → ↑risk of hypoglycaemia [31] |
| VTE prophylaxis | All critically ill patients | LMWH or UFH unless contraindicated (active bleeding, severe thrombocytopenia). Mechanical prophylaxis if pharmacological C/I |
| Stress ulcer prophylaxis | ICU patients on vasopressors or mechanical ventilation | PPI or H₂ blocker — prevents stress-related mucosal disease |
| Transfusion | Hb < 7 g/dL (restrictive) | Trigger Hb 7 g/dL for most ICU patients (liberal transfusion strategy shows no benefit and may worsen outcomes) |
Infection Source Control
Prompt identification and treatment of primary sites of infection are the primary therapeutic intervention — most other interventions are supportive only [1]. Source control means:
- Drain abscesses (percutaneous or surgical)
- Remove infected foreign bodies (lines, catheters, prostheses)
- Debride necrotic tissue (necrotising fasciitis)
- Decompress obstructed systems (biliary, urinary)
15% of cholangitis patients will NOT respond to antibiotics and require emergency biliary decompression [13] — ERCP → PTBD → ECBD
PILLAR 2: Source-Specific Treatment
This is the definitive treatment. The antibiotic choice depends on the suspected source, likely organisms, and local resistance patterns.
When the source is unknown:
| Scenario | Empirical Regimen | Rationale |
|---|---|---|
| P. aeruginosa unlikely | Vancomycin + ONE of: piperacillin-tazobactam (Tazocin), ceftriaxone/cefotaxime, or carbapenem (imipenem/meropenem) [1] | Vancomycin covers MRSA. The second agent covers Gram-negatives and anaerobes |
| P. aeruginosa likely (hospital-acquired, ICU, immunocompromised, recent Abx) | Vancomycin + TWO of: anti-pseudomonal β-lactam (piperacillin-tazobactam), anti-pseudomonal cephalosporin (ceftazidime/cefepime), anti-pseudomonal carbapenem (imipenem/meropenem), fluoroquinolone (ciprofloxacin), aminoglycoside (gentamicin/amikacin), or monobactam (aztreonam) [1] | Double anti-pseudomonal coverage because Pseudomonas has high intrinsic resistance and rapidly develops further resistance |
Why vancomycin empirically? S. aureus infection is associated with significant morbidity if not treated early. Increasing causes of sepsis are due to MRSA, so vancomycin is used until the possibility of MRSA sepsis has been excluded [1]. Once cultures show a susceptible organism, de-escalate.
| Source | Empirical Regimen | Duration | Key Principles |
|---|---|---|---|
| CAP — Outpatient | PO augmentin ± macrolide or doxycycline [5] | 5–7 days | Cover S. pneumoniae (most common) ± atypicals |
| CAP — Hospitalized, mild-moderate | IV augmentin ± macrolide/doxycycline [5] | 7–10 days | In all CAP, cover S. pneumoniae. In severe CAP, cover Legionella [5]. Severity guided by CURB-65 |
| CAP — Severe/ICU | IV ceftriaxone/cefotaxime + macrolide/fluoroquinolone | 7–14 days | Broader cover including Legionella (macrolide or fluoroquinolone), severe Gram-negatives |
| Uncomplicated cystitis — Female | Nitrofurantoin 100 mg BD × 5 days OR trimethoprim 200 mg BD × 3 days | 3–5 days | First-line agents with narrow spectrum to minimize resistance |
| Acute pyelonephritis | IV augmentin → tazocin if suspect Pseudomonas → imipenem/meropenem if severe/rapidly deteriorating. IV until afebrile 24–48h → complete 14 days with oral [19] | 14 days | Hospitalize if severe or suspicious of obstruction [19]. CT abdomen if no improvement > 72h |
| Acute prostatitis | Quinolone (e.g. ciprofloxacin/levofloxacin) for 2–6 weeks [6] | 2–6 weeks | Quinolones preferred for excellent prostatic penetration [6] — most other antibiotics penetrate the prostate poorly due to the blood-prostate barrier |
| Cholangitis | IV augmentin or ceftriaxone + metronidazole → adjust based on bile/blood culture | Until drainage achieved + 5–7 days | Biliary decompression is essential: ERCP (1st line) → PTBD → surgical ECBD [13]. Continuous monitoring of vitals for signs of failure: ↑temperature/pulse, ↓BP/consciousness/urine output, increased abdominal tenderness [13] |
| Liver abscess — Pyogenic | IV augmentin or ceftriaxone + metronidazole for at least 4–6 weeks (IV for first 2 weeks → oral for 4 weeks) [4][7] | 4–6 weeks total [4] | Percutaneous drainage: USG/CT-guided, diagnostic + therapeutic. Needle aspiration if < 5 cm, catheter placement if > 5 cm [4]. For Klebsiella liver abscess: meningitic dose ceftriaxone (2g Q12H) [4] |
| Liver abscess — Amoebic | Metronidazole 750 mg TDS × 7–10 days → followed by luminal agent (paromomycin or diloxanide furoate) | 7–10 days + luminal | Usually not needed for percutaneous drainage — antimicrobials alone are sufficient for amoebic abscess [4]. Luminal agent kills cysts in the gut to prevent relapse |
| Meningitis — Empirical | Empirical Abx ≤ 6h ± dexamethasone → should NOT be delayed for CT brain [8]. IV ceftriaxone 2g Q12H + IV ampicillin (if Listeria risk: elderly, immunocompromised, neonates) + IV dexamethasone 0.15 mg/kg Q6H × 4 days (started before or with first dose of antibiotics) | 7–21 days depending on organism | Dexamethasone ↓mortality in pneumococcal meningitis by reducing inflammation. Must be given before or with first Abx dose — if given later, benefit lost |
| TB meningitis | Standard anti-TB: RHZE for 2 months → RH for 10 months (total 12 months for TBM) + adjunctive dexamethasone | 12 months | Steroids reduce mortality in TBM by ↓cerebral oedema and inflammation |
| IE — Native valve | Empirical: IV flucloxacillin + gentamicin (if acute, suspect S. aureus). IV benzylpenicillin + gentamicin (if subacute, suspect viridans strep) → adjust to organism | 4–6 weeks IV | Blood cultures × 3 before antibiotics [9]. Prolonged IV therapy because bacteria in vegetations are in a "biofilm" state with slow metabolic activity — need sustained bactericidal drug levels |
| Cellulitis / Erysipelas | IV penicillin/ampicillin + IV cloxacillin (1st line). Alternative: augmentin/unasyn. If CA-MRSA suspected: PO septrin or IV vancomycin [10] | 5–14 days | In HK, 50–80% of GAS are resistant to clindamycin [10] — avoid as first-line |
| Neutropenic fever — Low risk | PO ciprofloxacin 750 mg BD + augmentin 1g BD [2] | Until ANC recovery and afebrile ≥ 48h | Low risk: neutropenia ≤ 7 days + no or few comorbidities |
| Neutropenic fever — High risk | IV ceftazidime 1–2g Q8H or cefepime 2g Q12H, or tazocin 4.5g Q6–8H, or imipenem/meropenem [2] | Minimum until afebrile ≥ 48h + ANC > 0.5 | Add aminoglycoside for ill cases; vancomycin if MRSA/skin/catheter infection suspected; amphotericin B if no response after 5 days and culture negative [2]. G-CSF: controversial, not routinely recommended but may be considered in septic shock, fungal infection, or severe pneumonia [2] |
Antibiotic Timing Is Everything
Antibiotics should be administered within the first 6 hours of presentation or earlier, after obtaining blood culture [1]. In septic shock, the target is even tighter — within 60 minutes. Each hour of delay increases mortality. However: always take blood cultures FIRST. The brief delay to draw cultures (2–5 minutes) is vastly offset by the benefit of identifying the organism.
PILLAR 3: Supportive Care and Symptomatic Treatment
Should you treat fever? This is nuanced:
| Situation | Recommendation | Rationale |
|---|---|---|
| Most febrile patients | Antipyretics for comfort (not mandatory to normalize temperature) | Fever is adaptive. No evidence that routine antipyretic therapy improves outcomes in most infections. Treat for patient comfort and to reduce metabolic demand |
| Limited cardiorespiratory reserve (CHF, COPD, elderly) | Actively treat fever | Each 1°C ↑ raises O₂ consumption by 10–12.5% and HR by 8–10 bpm → may precipitate cardiac ischaemia or decompensation |
| Febrile seizure history (paediatric) | Antipyretics ± tepid sponging | Evidence that antipyretics prevent febrile seizures is weak, but standard practice |
| Neurological injury (stroke, TBI) | Antipyretic medications should be administered to lower temperature in hyperthermic patients with stroke [31] | Fever worsens neurological outcomes by ↑metabolic demand on ischaemic penumbra. Source of hyperthermia should be identified and treated [31] |
| Hyperthermia (heat stroke, MH, NMS) | Physical cooling is essential — antipyretics do NOT work | No pyrogen-mediated set-point elevation → NSAIDs/paracetamol target COX/PGE₂ pathway which is not activated. Active cooling: ice packs, evaporative cooling, cold IV fluids, dantrolene for MH |
Antipyretic agents:
| Agent | Mechanism | Dose | Key Points |
|---|---|---|---|
| Paracetamol (acetaminophen) | Inhibits COX in the CNS (predominantly COX-2) → ↓PGE₂ synthesis in hypothalamus → ↓set-point. Also activates descending serotonergic pathways. Weak peripheral anti-inflammatory effect | 500 mg–1g PO/IV Q4–6H, max 4g/day | First-line antipyretic. C/I: severe hepatic impairment (paracetamol is hepatotoxic in overdose via NAPQI accumulation when glutathione is depleted). ↓Max dose to 2g/day in liver disease |
| NSAIDs (ibuprofen, naproxen) | Inhibit COX-1 and COX-2 → ↓PGE₂ synthesis both centrally and peripherally → antipyretic + anti-inflammatory + analgesic | Ibuprofen 200–400 mg PO Q6–8H | Anti-inflammatory as well as antipyretic. C/I: peptic ulcer disease, GI bleeding, CKD, heart failure, aspirin-exacerbated respiratory disease. DO NOT give NSAIDs in myocarditis (↓PG production may worsen myocardial function + ↑myocardial necrosis) [32]. Avoid in dengue (↑bleeding risk from thrombocytopenia) |
| Aspirin | COX-1/2 inhibitor | 300–600 mg PO Q4–6H | Used for antipyresis in specific situations (e.g. rheumatic fever, Kawasaki disease). C/I in children < 16 years: Reye syndrome (aspirin + viral illness → hepatic mitochondrial dysfunction → acute liver failure + encephalopathy) |
Physical Cooling Measures
Physical methods work by directly removing heat from the body surface without affecting the hypothalamic set-point:
- Tepid sponging (lukewarm water, NOT cold — cold causes vasoconstriction and shivering, which paradoxically ↑heat generation)
- Fanning
- Cooling blankets
- Ice packs to groin and axillae (where large vessels are superficial)
- IV cold crystalloid (4°C) for severe hyperthermia
These are essential in hyperthermia (where antipyretics don't work) and adjunctive in fever.
| Situation | Approach | Rationale |
|---|---|---|
| All febrile patients | Encourage oral fluids; IV fluids if unable to tolerate oral | Insensible losses ↑ ~200–500 mL/day per °C above normal (sweating + respiratory water loss). Dehydration → pre-renal AKI, ↓perfusion |
| Sepsis/septic shock | ≥ 30 mL/kg IV crystalloid within first 3 hours [14] → then guided by haemodynamic status | Vasodilation and capillary leak → intravascular depletion despite total body fluid excess. Balanced crystalloids (Ringer's lactate/Plasmalyte) preferred over 0.9% NaCl (↓hyperchloraemic acidosis and renal injury) [14] |
| Dehydration from GI losses | Oral rehydration solution (ORS) if mild-moderate; IV if severe/unable to tolerate oral | Replace established deficits + ongoing losses + daily maintenance |
| Scenario | Management | Key Points |
|---|---|---|
| Drug fever | Stop the offending drug — temperature typically resolves within 48–72 hours [3] | No specific treatment needed beyond drug cessation. If essential medication, consider desensitization or alternative agent. Drug fever from anti-TB drugs: exclude superinfection or worsening TB → suspend treatment and re-introduce drugs sequentially to identify offending agent ± oral steroids [33] |
| Thyrotoxic crisis (thyroid storm) | Close monitoring (CVP ± ICU). Supportive: paracetamol + physical cooling (NOT aspirin — displaces T₄ from TBG → ↑free T₄). Non-selective β-blocker (propranolol 40–80 mg Q4–6H PO). Thionamide (PTU preferred — blocks T₄→T₃ conversion). Glucocorticoids (IV hydrocortisone 200 mg stat, then 100 mg Q6–8H). Iodine after ≥ 1h of thionamide [34] | PTU preferred over methimazole in storm because it blocks both synthesis AND peripheral T₄→T₃ conversion. Iodine must be given ≥ 1h AFTER thionamide to prevent iodine from being used as substrate for new hormone synthesis [34] |
| Adrenal crisis | IV hydrocortisone 100 mg bolus → 50 mg Q6–8H. Aggressive IV fluid resuscitation (0.9% NaCl). Treat precipitating cause (infection, surgery). Do NOT wait for lab results to treat — treat on clinical suspicion [34] | Cortisol is essential for vascular tone. Without it → profound vasodilation → refractory hypotension. Hydrocortisone provides both glucocorticoid and mineralocorticoid activity |
| Alcohol withdrawal + fever | R/o alternative diagnosis (CNS infection, drug OD, metabolic derangement, liver failure). Supportive: NPO, correct volume deficits. Correct metabolic derangements (hypoGly, hypoK, hypoMg, hypoPO₄). Thiamine + glucose. Benzodiazepines (diazepam, lorazepam, chlordiazepoxide) for psychomotor agitation. Barbiturates or propofol for refractory DT [35][36] | Thiamine BEFORE glucose — glucose metabolism requires thiamine as cofactor. Giving glucose without thiamine in a thiamine-depleted alcoholic can precipitate Wernicke's encephalopathy |
| Transfusion reaction (febrile non-haemolytic) | Stop transfusion. Paracetamol. Exclude acute haemolytic reaction (check for haemoglobinuria, repeat crossmatch, DAT). Resume if FNHTR confirmed and symptoms resolve | FNHTR is caused by cytokines accumulated in stored blood products and recipient Ab against donor leukocyte antigens. Pre-medication with paracetamol and using leukodepleted products reduces recurrence |
| Fever in SLE | NSAIDs, paracetamol ± low-to-moderate dose steroids. MUST rule out underlying infective or drug-related causes if unresponsive [37] | SLE patients are immunocompromised (disease + treatment) → infection is the most common cause of death in early SLE. Never assume fever is "just a flare" without excluding infection |
| Factitious fever | Compassionate, non-confrontational approach. Psychiatric evaluation. Avoid unnecessary invasive investigations | Confrontation often drives the patient away. Address underlying psychiatric pathology (personality disorder, factitious disorder, Munchausen syndrome) |
Source of hyperthermia should be identified and treated. Antipyretic medications should be administered to lower temperature in hyperthermic patients with stroke. Antibiotics should be started as required for possible infections such as pneumonia or urinary tract infections. Routine use of prophylactic antibiotics has NOT shown to be beneficial [31].
Special Management Situations
Management follows the diagnostic timing (5 W's) already described:
| Source | Management |
|---|---|
| Wind (atelectasis) | Incentive spirometry, deep breathing exercises, early mobilization, chest physiotherapy. Antibiotics NOT indicated for atelectasis alone |
| Water (UTI) | Remove catheter ASAP if still in situ. Empirical antibiotics if symptomatic. Recommend 1 week treatment for cystitis in elderly [6] |
| Water (anastomotic leak) | Surgical emergency → urgent CT abdomen, NPO, IV antibiotics, reoperation for repair or diversion |
| Wound (SSI) | Open wound, drain pus, irrigate. Antibiotics ± VAC therapy. Consider re-exploration if deep infection |
| Walking (DVT/PE) | Anticoagulation (LMWH → warfarin or DOAC). Prevention: early mobilisation, compression stockings/SCD, LMWH [12] |
| Wonder drugs | Stop offending drug. Observe for 48–72h. For malignant hyperthermia: dantrolene IV (specific antidote — blocks ryanodine receptor → ↓intracellular Ca²⁺ release from sarcoplasmic reticulum → ↓sustained muscle contraction and thermogenesis). For NMS: stop offending agent (antipsychotic/antiemetic) + dantrolene + bromocriptine (D₂ agonist) |
A medical emergency as unchecked proliferation of bacteria can lead to rapid progression into septic shock, especially in Gram-negative sepsis [2]
Principle: Timely (< 1–2h) administration of broad-spectrum, bactericidal antibiotics with minimal toxicity, covering most pathogens especially P. aeruginosa [2]
| Risk Category | Criteria | Empirical Regimen |
|---|---|---|
| Low risk | Neutropenia ≤ 7 days, no or few comorbidities | PO ciprofloxacin 750 mg BD + augmentin 1g BD. Levofloxacin 750 mg QD PO if penicillin allergy [2] |
| High risk | ANC ≤ 0.1 for > 7 days, shock, pneumonia, new abdominal pain or CNS signs [2] | IV monotherapy: ceftazidime 1–2g Q8H or cefepime 2g Q12H or tazocin 4.5g Q6–8H or imipenem/meropenem [2] |
Add-on therapy for selected cases [2]:
- Aminoglycoside (amikacin 15 mg/kg Q24H IV) for ill patients
- Vancomycin 500 mg Q6H or 1g Q12H if culture positive or highly suggestive of MRSA, skin or catheter infection
- Amphotericin B 0.5–1 mg/kg/day if no response after 5 days and culture negative (empirical antifungal cover — prolonged neutropenia ↑risk of invasive fungal infection)
Specific antibiotic therapy after C/ST results [2]
G-CSF [2]: Controversial and not recommended in latest guidelines (but often given). Some evidence of increasing inflammatory response. Can be considered if septic shock, fungal infection, or severe pneumonia. If given, stop when neutrophil count returns to 1 [2]
Buffy coat (WBC) transfusion [2]: Must be irradiated to prevent TA-GVHD. Indication: neutropenic fever (ANC < 0.5) PLUS documented infection not responding to broad-spectrum Abx + antifungal for ≥ 48h. Dose: 10U/day for ≥ 4 days until fever subsides [2]
Continuous monitoring of vitals to look for signs of failure of conservative treatment [13]:
- ↑Temperature/Pulse
- ↓BP/Consciousness level/Urine output
- Increased abdominal tenderness and guarding [13]
Management of sepsis: recognize signs of shock. Supportive treatment such as fluid resuscitation to prevent multiorgan failure [13]
Biliary decompression and drainage: 15% of patients will NOT respond to antibiotics [13]:
- Endoscopic = ERCP (1st line)
- Radiologic (percutaneous) = PTBD / percutaneous cholecystostomy
- Surgical = ECBD / bypass / resection
- QMH practice: ERCP → PTBD → ECBD [13]
Definitive treatment should be deferred until cholangitis has been treated and the proper diagnosis is established [13]
| Drug | Key Contraindications | Why |
|---|---|---|
| Paracetamol | Severe liver disease, active liver failure | Hepatotoxic via NAPQI metabolite; depleted glutathione in liver disease → ↑toxicity |
| NSAIDs | Peptic ulcer, GI bleeding, CKD, CHF, myocarditis [32], dengue, pregnancy (3rd trimester) | ↓Renal PG → ↓GFR, ↓gastric mucosal protection, fluid retention, platelet dysfunction, ↑myocardial necrosis |
| Aspirin | Children < 16 years (Reye syndrome), dengue, active bleeding | Irreversible COX-1 inhibition → platelet dysfunction; Reye syndrome in children with viral illness |
| Starch-based colloids | Sepsis resuscitation | Associated with ↑renal failure without survival benefit [14] |
| Dopamine | No longer 1st line for septic shock | Higher arrhythmia risk than norepinephrine |
| G-CSF | Not routinely in neutropenic fever | May ↑inflammatory response; reserve for specific indications [2] |
| PTU (propylthiouracil) | Prior agranulocytosis from thionamide | Use lithium as alternative [34] |
| Aspirin in thyroid storm | Displaces T₄ from TBG → ↑free T₄ | Use paracetamol instead [34] |
High Yield Summary — Management of Fever/Chills
Three pillars: (1) Resuscitate, (2) Find and treat the source, (3) Supportive care.
Sepsis Hour-1 Bundle: Lactate, blood cultures BEFORE Abx, broad-spectrum IV Abx within 60 min, 30 mL/kg crystalloid if hypotension/lactate ≥ 4, vasopressors if MAP < 65 after fluids.
Vasopressor: Norepinephrine 1st line. Vasopressin or epinephrine added if needed. Dobutamine for low CO with adequate filling. Crystalloid (balanced preferred), NO starch colloids.
Empirical Abx for unknown source: Vancomycin + piperacillin-tazobactam/ceftriaxone/carbapenem. Add double anti-pseudomonal if Pseudomonas likely.
Neutropenic fever: Medical emergency. Low risk: PO cipro + augmentin. High risk: IV ceftazidime/cefepime/tazocin/carbapenem. Add vanco for MRSA, amphotericin B if no response after 5 days.
Cholangitis: Abx + biliary decompression (ERCP → PTBD → ECBD). 15% fail antibiotics alone.
Liver abscess: Abx 4–6 weeks + percutaneous drainage (< 5cm needle, > 5cm catheter). Klebsiella: meningitic-dose ceftriaxone + eye consult. Amoebic: metronidazole alone usually sufficient.
Antipyretics: Paracetamol 1st line. NSAIDs C/I in myocarditis, dengue, CKD, GI bleeding. Aspirin C/I in children (Reye) and thyroid storm (↑free T₄). Physical cooling essential in hyperthermia.
Do NOT delay Abx for investigations. Blood cultures BEFORE antibiotics → give antibiotics → then LP/imaging.
Active Recall - Management of Fever/Chills
References
[1] Senior notes: felixlai.md (Sepsis treatment, pp. 37–41) [2] Senior notes: Ryan Ho Haemtology.pdf (Neutropenic fever management, pp. 71) [3] Lecture slides: murtagh merge.pdf (Fever that is prolonged — drug idiosyncrasies, p. 53) [4] Senior notes: maxim.md (Liver abscess management, p. 258) [5] Senior notes: Ryan Ho Respiratory.pdf (CAP management and empirical Abx, p. 64) [6] Senior notes: Ryan Ho Urogenital.pdf (Prostatitis and UTI in elderly, p. 128) [7] Senior notes: felixlai.md (Liver abscess treatment, p. 438) [8] Senior notes: Ryan Ho Neurology.pdf (Meningitis management — empirical Abx timing, p. 145) [9] Senior notes: Ryan Ho Cardiology.pdf (IE approach — blood cultures, p. 149) [10] Senior notes: Ryan Ho Rheumatology.pdf (Cellulitis management, p. 136) [12] Senior notes: maxim.md (Post-op fever — DVT prevention, p. 64) [13] Senior notes: felixlai.md (Cholangitis treatment, pp. 522) [14] Senior notes: Ryan Ho Critical Care.pdf (Septic shock management — Surviving Sepsis, pp. 22–23) [19] Senior notes: Ryan Ho Urogenital.pdf (Pyelonephritis management, p. 127) [31] Senior notes: felixlai.md (Fever management in stroke, pp. 1150, 1156) [32] Senior notes: Ryan Ho Cardiology.pdf (Myocarditis — NSAIDs contraindicated, p. 165) [33] Senior notes: Ryan Ho Respiratory.pdf (Anti-TB drug fever, p. 88) [34] Senior notes: Ryan Ho Endocrine.pdf (Thyrotoxic crisis management, p. 14) [35] Senior notes: Ryan Ho GI.pdf (Alcohol withdrawal management, p. 303) [36] Senior notes: Ryan Ho Psychiatry.pdf (Alcohol withdrawal management, p. 106) [37] Senior notes: Ryan Ho Rheumatology.pdf (SLE fever management, p. 77)
Complications of Fever/Chills
Complications of fever/chills can be divided into two broad categories:
- Complications of the fever itself — direct consequences of elevated body temperature and the systemic inflammatory response
- Complications of the underlying cause — organ-specific damage from whatever is driving the fever (infection, inflammation, malignancy)
In clinical practice, these overlap heavily. Sepsis, for example, produces both fever-related metabolic stress and infection-mediated organ damage simultaneously. The key insight is: most serious complications arise from the underlying cause, not the fever per se. Fever itself is rarely lethal unless it reaches hyperpyrexic levels (> 41°C) or occurs in patients with limited physiological reserve.
A. Direct Complications of Fever
These occur because fever is metabolically expensive — it demands more from the heart, lungs, brain, and kidneys than the body may be able to deliver.
- Epidemiology: Affect 2–5% of children aged 6 months to 5 years. Most common neurological disorder in childhood
- Pathophysiology: Not fully understood, but elevated temperature lowers the seizure threshold in the immature brain. IL-1β acts directly on hippocampal neurons to increase neuronal excitability. Genetic susceptibility plays a major role (strong family clustering)
- Classification:
- Simple febrile seizure (70–75%): generalized, < 15 minutes, single episode in 24 hours, no postictal focal deficits. Excellent prognosis — does NOT increase epilepsy risk significantly
- Complex febrile seizure: focal features, > 15 minutes, or recurrent within 24 hours. Slightly ↑ risk of subsequent epilepsy (~2–4% vs 1% baseline)
- Management: Acute management of the seizure (ABC, recovery position, benzodiazepine if prolonged > 5 minutes). Investigate for cause of fever (especially meningitis in < 12 months). Antipyretics for comfort but do NOT reliably prevent febrile seizures
- Prognosis: 30–40% recurrence risk. Risk of subsequent epilepsy is only 1–2% after simple febrile seizure (essentially same as general population)
- Mechanism: Fever increases insensible fluid losses by ~200–500 mL/day per °C above normal through:
- ↑Sweating (particularly during defervescence)
- ↑Respiratory water loss from tachypnoea
- ↓Oral intake from anorexia and malaise (TNF-α-mediated)
- Consequences: Pre-renal AKI (↓renal perfusion → ↑urea disproportionate to creatinine), electrolyte derangement (hyponatraemia from ADH release, hypokalaemia from sweating/vomiting)
- Vulnerable groups: Elderly (↓thirst sensation, ↓renal concentrating ability), infants (high body surface area:volume ratio → ↑insensible losses), patients with heart failure or CKD
- Mechanism: Each 1°C rise increases O₂ consumption by 10–12.5%, heart rate by 8–10 bpm, and cardiac output proportionally. This is tolerated well by healthy individuals but can overwhelm those with limited reserve.
- Consequences:
- Acute coronary syndrome: ↑O₂ demand may outstrip supply in patients with coronary stenosis → demand ischaemia
- Cardiac arrhythmia: especially AF, triggered by adrenergic surge and electrolyte disturbance [38]
- Decompensated heart failure: ↑cardiac workload in a failing heart → acute pulmonary oedema
- Clinical pearl: This is why fever should be actively treated in patients with limited cardiorespiratory reserve, even though it is adaptive in most healthy individuals
- Definition: Temperature > 41°C — a medical emergency regardless of cause
- Pathophysiology: At extreme temperatures, proteins begin to denature, cellular membranes destabilize, and enzymatic function fails. Direct thermal injury to endothelial cells triggers DIC-like coagulopathy
- Consequences: Rhabdomyolysis (muscle cell destruction → myoglobinaemia → AKI from myoglobin cast nephropathy), hepatic necrosis, cerebral oedema, DIC, multi-organ failure
- Key causes: Heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, severe CNS infection, drug reactions (including malignant hyperthermia: with FHx, can be delayed up to 24 hours post-op, common agents include suxamethonium [12])
- Management: Aggressive physical cooling — ice packs, evaporative cooling, cold IV fluids, dantrolene for malignant hyperthermia (blocks ryanodine receptors → ↓sarcoplasmic Ca²⁺ release → ↓muscle contraction and heat generation)
- Mechanism: Fever is a common precipitant of delirium, especially in the elderly and those with pre-existing cognitive impairment. The mechanisms are multifactorial:
- Cytokines (IL-1, TNF-α) disrupt BBB integrity → neuroinflammation
- Altered neurotransmitter metabolism (↑tryptophan → serotonin pathway disruption, ↓acetylcholine)
- Dehydration and electrolyte imbalance compound cerebral metabolic stress
- Clinical significance: Delirium is an independent predictor of mortality (14% at 1 month, 22% at 6 months) [36]. Delirium can be the only presenting sign of serious infection in the elderly
- Management: Treat the underlying cause of fever; supportive care; avoid deliriogenic medications; non-pharmacological measures first; haloperidol or low-dose atypical antipsychotics only if patient is a danger to self or others [36]
- Hypermetabolism: Fever accelerates catabolism — ↑protein breakdown from skeletal muscle (providing amino acids for gluconeogenesis and acute phase protein synthesis), ↑lipolysis. Prolonged fever → muscle wasting, weight loss, negative nitrogen balance
- Hypoglycaemia: Particularly in neonates, malnourished patients, and liver disease. Glycogen stores are rapidly depleted under hypermetabolic stress
- Anaemia of inflammation: IL-6 → ↑hepcidin → sequesters iron in macrophages → ↓iron availability for erythropoiesis. TNF-α suppresses erythropoietin production. This develops over days to weeks in sustained fever
When fever is caused by infection and the host response becomes dysregulated, the complications escalate dramatically. This is the sepsis → septic shock → MODS continuum [1][14].
Multiple Organ Dysfunction Syndrome (MODS)
Progressive organ dysfunction in an acutely ill patient such that homeostasis cannot be maintained without intervention [1]. MODS is the most feared complication of severe infection and the leading cause of ICU mortality.
The pathophysiology is a vicious cycle: infection → cytokine storm → endothelial activation → microvascular dysfunction → tissue hypoxia → organ failure → further inflammation.
| System | Complication | Pathophysiology | Key Features |
|---|---|---|---|
| Respiratory | ARDS [1][14] | Cytokine-mediated ↑alveolar-capillary permeability → protein-rich oedema fluid floods alveoli → impaired gas exchange + ↓lung compliance. Hyaline membrane formation | Acute onset, bilateral opacities on CXR not fully explained by effusion/cardiac failure, PaO₂/FiO₂ ≤ 300 despite PEEP [14]. Non-cardiogenic pulmonary oedema → type 1 respiratory failure. Requires mechanical ventilation with lung-protective strategy (low tidal volume 6 mL/kg) |
| Cardiovascular | Septic shock [1][14] | iNOS induction → massive NO release → vasodilation → ↓SVR. Capillary leak → third-spacing → ↓intravascular volume. Sepsis-induced myocardial depression (cytokines depress myocardial contractility directly) | MAP < 65 despite fluids, requiring vasopressors + lactate > 2 mmol/L [14]. Mortality 40–50% |
| Renal | Acute tubular necrosis / AKI [1] | Renal hypoperfusion (↓MAP) + direct cytokine-mediated tubular injury + microvascular dysfunction → ischaemia of PCT → ATN. FENa is increased (tubular damage → failure to reabsorb sodium) [14] | Oliguria/anuria, ↑creatinine, ↑urea, metabolic acidosis. May require renal replacement therapy (CRRT in ICU) |
| Hepatic | Jaundice / GI bleeding / Paralytic ileus [1] | Hepatic hypoperfusion → "shock liver" (centrilobular necrosis → ↑↑AST/ALT). Kupffer cell activation → ↑bilirubin processing dysfunction → cholestatic jaundice. Splanchnic hypoperfusion → stress ulceration → GI bleeding. Autonomic dysfunction → ↓bowel motility → ileus | ↑Bilirubin, ↑ALT/AST (can be massively ↑ in ischaemic hepatitis), ↓albumin, ↑PT/INR (synthetic failure) |
| Neurological | Septic encephalopathy / Critical illness polyneuropathy [1] | Septic encephalopathy: cytokine-mediated BBB disruption, altered neurotransmitter metabolism, cerebral microvascular dysfunction. CIP/CIM: axonal degeneration of peripheral nerves (CIP) and myopathy (CIM) from inflammation + disuse + metabolic derangement | Altered mental status, obtundation, restlessness [1]. CIP/CIM: diffuse weakness, difficulty weaning from ventilator, ↓reflexes. Diagnosed by EMG/NCS. Recovery is slow (months) |
| Haematological | DIC [1] | Tissue factor release from damaged endothelium and monocytes → activation of coagulation cascade → widespread microvascular thrombi → consumption of clotting factors and platelets → paradoxical bleeding | ↑PT/aPTT, ↓fibrinogen, ↑D-dimer, ↓platelets, schistocytes on PBS. Clinical: simultaneous thrombosis (organ ischaemia, skin necrosis, purpura fulminans) AND bleeding (oozing from venepuncture sites, mucosal haemorrhage) |
The Paradox of DIC
DIC is one of the most counterintuitive conditions in medicine: the patient is simultaneously clotting too much (microvascular thrombi → organ damage) AND bleeding (consumption of platelets and clotting factors). Why? Because the coagulation cascade is activated systemically and uncontrollably rather than locally at a wound site. The microthrombi consume clotting factors faster than the liver can replace them → eventually, nothing is left to form normal haemostatic plugs at wound sites → bleeding ensues.
C. Complications of Specific Fever-Causing Conditions
The complications are driven by the underlying aetiology. Here are the high-yield organ-specific and condition-specific complications:
| Condition | Complications | Pathophysiology |
|---|---|---|
| Pneumonia | Respiratory failure; lung abscess; septicaemia with multi-organ failure; parapneumonic effusion ± empyema; electrolyte abnormalities (hypoNa due to SIADH); cardiac complications (acute MI, arrhythmia, especially AF) [38] | Pneumonia → alveolar inflammation → impaired gas exchange (V/Q mismatch). Necrosis of lung parenchyma → abscess. Infected pleural fluid → empyema (pH < 7.2, glucose < 2.2 mmol/L, LDH > 1000). ADH released from inflamed lung tissue → dilutional hyponatraemia. Systemic inflammation → AF (most common arrhythmia triggered by acute illness) |
| TB meningitis | Basal meningeal adhesions → CN palsies (III, IV, VI, VIII), hydrocephalus; infarction due to endarteritis obliterans; parenchymal damage; spinal spread → myelitis, arachnoiditis, paraparesis; SIADH → hyponatraemia [8] | TB produces thick basilar exudate → encases cranial nerves at base of brain → CN palsies. Exudate blocks CSF outflow at cisterns → communicating hydrocephalus. Endarteritis obliterans = inflammation of vessel wall → intimal proliferation → thrombosis → ischaemic infarction. Think TBM in CN palsy combinations that don't make sense [8] |
| Condition | Complications | Pathophysiology |
|---|---|---|
| Liver abscess | Rupture (especially if large > 6 cm or cirrhosis) → subphrenic abscess, rupture into viscera, IVC or kidney; pleuropulmonary complications (15–20%): pleurisy, pleural effusion, empyema; Budd-Chiari syndrome from local compression [4][7] | Large abscess → capsular necrosis → rupture into adjacent structures. Diaphragmatic inflammation from right lobe abscess → sympathetic pleural effusion, diaphragmatic paralysis. Direct compression of hepatic veins → hepatic venous outflow obstruction (Budd-Chiari) |
| Klebsiella liver abscess | Endogenous endophthalmitis; meningitis [4] | Klebsiella pneumoniae (hypermucoviscous strains with K1/K2 capsular serotypes) has unique ability to cause metastatic septic seeding even from a primary liver abscess → haematogenous spread to eyes (endophthalmitis → blindness if untreated) and CNS (meningitis). Urgent eye consult if symptoms of endophthalmitis [4] |
| Amoebic liver abscess | Rupture + peritonitis (2–7%); pleuropulmonary involvement (pleural effusion, bronchopleural fistula); rupture into pericardium (especially left lobe abscess, associated with very high mortality) [7] | Left lobe abscess sits adjacent to the pericardium → rupture through the diaphragm → amoebic pericarditis → tamponade → death. This is why left lobe amoebic abscesses warrant more aggressive drainage |
| Cholangitis | Septic shock → multi-organ failure (Reynold's pentad); hepatic abscess; cholangiohepatitis [13] | Biliary obstruction → stasis → bacterial overgrowth → ↑intraluminal pressure → cholangiovenous reflux (bacteria forced into bloodstream through disrupted bile duct epithelium) → bacteraemia → sepsis. 15% fail antibiotics and develop suppurative cholangitis |
Complications of pyelonephritis, especially if obstruction, recent instrumentation, prior urinary tract abnormalities, DM, or immunocompromised [19]:
- Spread of infection: renal corticomedullary abscess, perinephric abscess [19] — infected material breaches renal capsule → perinephric fat → retroperitoneal abscess
- Urosepsis: systemic sepsis, shock, multi-organ failure [19] — Gram-negative bacteraemia (E. coli, Klebsiella) releases LPS → massive cytokine response → distributive shock
- Acute renal failure [19] — combination of sepsis-mediated AKI and obstructive uropathy if stones or other obstruction present
Complications mainly occur in pyogenic and chronic meningitis [8]:
- Basal meningeal adhesions from incomplete resolution of inflammatory exudates:
- Arteritis/thrombophlebitis → cerebral infarction [8] — inflammation of vessel walls (endarteritis) → luminal narrowing → thrombosis → ischaemic stroke
- Parenchymal damage [8]:
- Neurological sequelae: intellectual impairment, mental retardation, cerebral palsy — especially in neonatal/infant meningitis
- Seizures: 10% in acute bacterial meningitis, ~5% develop epilepsy [8]
- Spread of infection [8]:
- Locally → cerebritis, cerebral abscess, subdural effusion/empyema
- Systemically → arthritis, IE
- SIADH → hyponatraemia [8] — meningeal inflammation stimulates ADH release → water retention → dilutional hyponatraemia
Complications of IE (from septic embolism and immune complex deposition) [9]:
| Category | Complications | Pathophysiology |
|---|---|---|
| Septic embolism | Stroke, brain abscess, cold limbs (peripheral embolism), splenic/renal/visceral infarcts, septic pulmonary emboli (right-sided IE → multiple cavitating lesions on CXR) [9] | Friable vegetations fragment → embolize to cerebral, splenic, renal, mesenteric or pulmonary vasculature. Size of vegetation correlates with embolic risk (> 10 mm = high risk, especially on anterior mitral valve leaflet) |
| Immune complex deposition | Glomerulonephritis (RBC casts, proteinuria), Osler nodes (tender nodules on finger pulps — immune complex vasculitis), Roth spots (retinal haemorrhages with white centres) [9] | Sustained antigenaemia → polyclonal B-cell activation → circulating immune complexes → deposit in glomeruli (type III hypersensitivity → proliferative GN) and small vessels (digital arteries → Osler nodes) |
| Valvular destruction | New/worsening regurgitation, paravalvular abscess (AV block on ECG), heart failure | Direct bacterial invasion and enzymatic destruction of valve tissue → leaflet perforation, chordal rupture. Abscess extends to conduction system → AV block. Severe regurgitation → acute volume overload → heart failure |
Complications of cellulitis/erysipelas: bacteraemia, endocarditis, septic arthritis, osteomyelitis, sepsis, toxic shock syndrome (TSS) [10]
- Necrotising fasciitis is the most feared complication: infection spreads along fascial planes with rapid necrosis → pain out of proportion to examination findings is the classic early clue. Surgical emergency — requires urgent debridement, not just antibiotics
DVT/PE — the "Walking" complication [12]:
- First sign of DVT/PE may be unexplained tachycardia; 60–80% are clinically silent [12]
- D-dimer is NOT useful in the post-operative setting — elevated from surgery itself [12]
- Fatal PE accounts for ~5% of post-operative deaths and is largely preventable
Anastomotic leak — becomes apparent 5–7 days postoperatively [39]:
- Clinical signs include pain, fever, tachycardia, feculent or purulent drainage [39]
- Management: fluid resuscitation, broad-spectrum IV antibiotics, bowel rest, image-guided drainage, ± temporary faecal diversion or re-operation
These are iatrogenic complications that arise from the therapies used to manage fever and its causes:
| Treatment | Complication | Mechanism |
|---|---|---|
| Paracetamol | Hepatotoxicity (overdose) | CYP450 metabolizes paracetamol → toxic metabolite NAPQI → normally conjugated by glutathione. In overdose or liver disease → glutathione depletion → NAPQI accumulates → centrilobular hepatic necrosis |
| NSAIDs | GI bleeding, AKI, cardiovascular events | ↓COX-1 → ↓gastric mucosal PGE₂ → ↓mucus/bicarbonate secretion → erosions/ulcers. ↓Renal PGs → ↓afferent arteriolar dilation → ↓GFR → pre-renal AKI. ↓PGI₂ (vasodilator) without ↓TXA₂ → pro-thrombotic state |
| Antibiotics | C. difficile colitis, drug resistance, drug fever, allergic reactions | Broad-spectrum antibiotics disrupt normal gut flora → overgrowth of toxigenic C. difficile → toxin A (enterotoxin) and toxin B (cytotoxin) → mucosal inflammation → pseudomembranous colitis. Easily missed cause of fever: C. diff colitis [12] |
| Anti-TB drugs | Hepatotoxicity (5.3–12% incidence); drug fever | Isoniazid, rifampicin, pyrazinamide are all potentially hepatotoxic. Withhold treatment if ALT ≥ 3× ULN or total bilirubin ≥ 2× ULN [33]. Drug fever: exclude superinfection or worsening TB → suspend treatment and re-introduce drugs sequentially [33] |
| Corticosteroids (used in septic shock, TBM, adrenal crisis) | Immunosuppression, hyperglycaemia, adrenal suppression, GI bleeding | Steroids suppress virtually all arms of immunity → ↑risk of secondary and opportunistic infections. ↑Gluconeogenesis → hyperglycaemia. Prolonged use → HPA axis suppression → risk of Addisonian crisis on abrupt withdrawal |
| IV fluids (aggressive resuscitation) | Fluid overload, pulmonary oedema, abdominal compartment syndrome | Capillary leak in sepsis means much of the infused crystalloid extravasates into interstitium → tissue oedema. Excessive resuscitation → IAP > 20 mmHg → abdominal compartment syndrome → ↓venous return, ↓renal perfusion, ↓diaphragmatic excursion |
| Vasopressors | Peripheral ischaemia, arrhythmia, extravasation injury | High-dose catecholamines → excessive vasoconstriction → digital/limb ischaemia, mesenteric ischaemia. Extravasation of norepinephrine → local tissue necrosis (must be given via central line) |
| Blood transfusion | Febrile non-haemolytic transfusion reaction, acute haemolytic reaction, TRALI, bacterial septic reaction, allergic reaction [40] | FNHTR: cytokines accumulated in stored products + Ab vs donor leukocyte Ag. TRALI: donor Ab vs recipient WBCs → activation in lung microvasculature → ARDS-like picture [40]. Bacterial contamination: rapid onset chills/rigors, high fever > 2°C, hypotension, DIC [40] |
C. difficile — The Hidden Complication
C. diff colitis is an easily missed cause of post-operative and post-antibiotic fever [12]. Any patient who develops fever + diarrhoea after a course of antibiotics (especially clindamycin, fluoroquinolones, cephalosporins, or broad-spectrum penicillins) should be tested for C. difficile toxin. Presentation ranges from mild diarrhoea to fulminant colitis with toxic megacolon, perforation, and death. Treatment: stop the offending antibiotic if possible; oral vancomycin 125 mg QDS × 10 days (first-line) or fidaxomicin 200 mg BD × 10 days.
| Sequela | Context | Mechanism |
|---|---|---|
| Post-infectious fatigue | EBV, COVID-19, influenza | Persistent immune activation, cytokine dysregulation, deconditioning. Up to 10% of EBV patients have fatigue lasting 6 months [17] |
| Long COVID | Post-COVID-19 | Physical, psychological and cognitive impairment after recovery — mechanism incompletely understood (persistent viral reservoirs, autoimmunity, endothelial dysfunction, microthrombi) [38] |
| Critical illness polyneuropathy/myopathy | Post-sepsis, prolonged ICU stay | Axonal degeneration (CIP) and myosin loss (CIM) from systemic inflammation, immobility, corticosteroids, neuromuscular blocking agents. Recovery takes months |
| Post-stroke depression | Stroke as complication of fever (IE, meningitis, septic emboli) | Prevalence 29%. Correlated with disability, anxiety, cognitive impairment, stroke severity [41] |
| Hearing loss | Post-meningitis (especially pneumococcal) | CN VIII involvement tends to persist [8] — sensorineural hearing loss from cochlear damage by inflammation/ischaemia. All children post-meningitis need audiometry |
| Post-sepsis syndrome | Post-ICU | Cognitive impairment, PTSD, chronic pain, recurrent infections, ↑cardiovascular risk. Affects up to 50% of sepsis survivors at 1 year |
High Yield Summary — Complications of Fever/Chills
Direct complications of fever: Febrile seizures (children 6mo–5y), dehydration/electrolyte disturbance, cardiovascular stress (↑O₂ demand → ACS/AF/decompensated HF), hyperpyrexia > 41°C (protein denaturation → rhabdomyolysis → DIC → MODS), delirium (especially elderly).
Sepsis → MODS: Respiratory (ARDS), Cardiovascular (septic shock), Renal (ATN/AKI), Hepatic (jaundice/GI bleed/ileus), Neurological (septic encephalopathy/CIP), Haematological (DIC).
DIC paradox: Simultaneous thrombosis (organ damage) AND bleeding (consumption of clotting factors).
Condition-specific complications:
- Pneumonia: respiratory failure, empyema, SIADH, arrhythmia (AF)
- TB meningitis: CN palsies, hydrocephalus, infarction (endarteritis), SIADH
- Liver abscess: rupture, pleuropulmonary complications, endophthalmitis (Klebsiella)
- IE: septic emboli (stroke, organ infarction), immune complex GN, valvular destruction → HF
- Pyelonephritis: perinephric abscess, urosepsis, AKI
- Meningitis: hydrocephalus, CN palsies, seizures/epilepsy, cerebral infarction, deafness
Iatrogenic complications: Paracetamol hepatotoxicity, NSAID GI/renal, antibiotic-associated C. diff, anti-TB hepatotoxicity, fluid overload from aggressive resuscitation, vasopressor-related ischaemia, transfusion reactions.
Active Recall - Complications of Fever/Chills
References
[1] Senior notes: felixlai.md (Sepsis — MODS, pp. 34–36) [4] Senior notes: maxim.md (Liver abscess complications, p. 258) [7] Senior notes: Ryan Ho GI.pdf (Liver abscess complications — pyogenic p. 237, amoebic p. 239) [8] Senior notes: Ryan Ho Neurology.pdf (Meningitis complications, pp. 142, 144, 145) [9] Senior notes: Ryan Ho Cardiology.pdf (IE presentation and complications, pp. 149) [10] Senior notes: Ryan Ho Rheumatology.pdf (Cellulitis complications, p. 135) [12] Senior notes: maxim.md (Post-op fever — DVT/PE, easily missed complications, pp. 61, 64) [13] Senior notes: felixlai.md (Cholangitis, pp. 521–522) [14] Senior notes: Ryan Ho Critical Care.pdf (Septic shock — MODS, ARDS, pp. 22–23) [17] Senior notes: Ryan Ho Respiratory.pdf (EBV complications, p. 53) [19] Senior notes: Ryan Ho Urogenital.pdf (Pyelonephritis complications, p. 127) [33] Senior notes: Ryan Ho Respiratory.pdf (Anti-TB drug complications, p. 88) [36] Senior notes: Ryan Ho Psychiatry.pdf (Delirium management and prognosis, p. 76) [38] Senior notes: Ryan Ho Respiratory.pdf (Pneumonia complications p. 65; COVID complications p. 58) [39] Senior notes: felixlai.md (Anastomotic leak, p. 706) [40] Senior notes: Ryan Ho Haemtology.pdf (Transfusion complications — bacterial septic reaction p. 150, TRALI p. 148) [41] Senior notes: felixlai.md (Post-stroke depression, p. 1163)
High Yield Summary
Definition: Fever = ↑hypothalamic set-point via PGE₂ → body actively heats (chills/rigors). Hyperthermia = set-point normal but heat gain > loss (antipyretics don't work).
Threshold: > 38°C (clinical); > 38.3°C (FUO, neutropenic fever). Hypothermia (< 36°C) can indicate severe sepsis.
Pyrogenic pathway: PAMPs/DAMPs → TLRs on macrophages → IL-1/IL-6/TNF-α → OVLT → COX-2 → PGE₂ → EP3 receptors → ↑set-point → vasoconstriction + shivering = fever + chills.
Post-op fever (5 W's): Wind (atelectasis, day 0-2), Water (UTI/anastomotic leak, day 3-5), Wound (SSI, day 5-7), Walking (DVT/PE, day 5+), Wonder drugs (drug fever, day 7-10). Also: Withdrawal, Wonky glands.
Sepsis-3 (2016): Sepsis = infection + SOFA ≥ 2. Septic shock = vasopressor for MAP ≥ 65 + lactate > 2. qSOFA: RR ≥ 22, sBP ≤ 100, altered GCS. SIRS criteria no longer define sepsis.
FUO: ≥ 38.3°C for ≥ 3 weeks, no diagnosis after appropriate workup. ~20% remain unknown.
HK-specific: TB (high prevalence), Klebsiella liver abscess (DM), dengue, S. suis (raw pork).
Key exam approach: History (travel, sexual, occupation, drugs, exposures, animal contact). Exam: skin, eyes, teeth, heart (murmur), lungs, abdomen (liver/spleen), LN, rectal/pelvic. Ix: CBC, CRP, ESR, blood culture, urine MC, CXR, LFT, RFT, lactate.
Relative bradycardia: Typhoid, Legionella, drug fever, lymphoma, factitious fever.
Rigors point toward bacteraemia, Gram-negative sepsis, cholangitis, malaria, abscess.
High Yield Summary — Differential Diagnosis of Fever/Chills
Default framework: Murtagh's strategy — probability diagnoses first (abscess, pneumonia, EBV, URTI, UTI), then serious-not-to-miss (infections: HIV, malaria, TB, IE, typhoid; cancers: lymphoma, leukaemia, RCC; vascular: vasculitides), then pitfalls (CTD, sarcoidosis, drug fever), then rarities (factitious fever).
Localizing approach: Respiratory → pneumonia/TB; Urinary → UTI/pyelonephritis; Abdominal → cholangitis/liver abscess; CNS → meningitis/encephalitis; Cardiac → IE/myocarditis; MSK → septic arthritis/osteomyelitis; Skin → cellulitis/SSI.
No localizing features: Use duration — acute (viral), subacute (abscess/IE/TB/typhoid), chronic (FUO framework).
HK-specific: TB (all unexplained fever!), Klebsiella liver abscess (DM), S. suis meningitis (raw pork), dengue, high HBV prevalence (HCC).
Post-op: 5 W's by timing. Neutropenic fever: medical emergency, 60-min door-to-antibiotic.
Paediatric "must-not-miss": Kawasaki disease (persistent fever > 5 days), rheumatic fever, meningitis, appendicitis, HSP.
Up to 20% of FUO remains unknown — this is a normal outcome, not a clinical failure.
High Yield Summary — Diagnostics for Fever/Chills
Sepsis-3: Infection + SOFA ≥ 2 = sepsis. Vasopressor for MAP ≥ 65 + lactate > 2 = septic shock. qSOFA (RR ≥ 22, sBP ≤ 100, altered GCS) for screening.
FUO: ≥ 38.3°C, ≥ 3 weeks, no diagnosis after appropriate workup. ~20% remain unknown. PET-CT is the game-changer investigation.
Neutropenic fever: ANC ≤ 0.5 × 10⁹/L + temp > 38.3°C (or > 38°C for > 1h). Medical emergency — empirical Abx within 60 min.
Basic fever screen (every patient): CBC with diff, ESR/CRP, blood cultures (≥ 2 sets before Abx), urine MC&S, CXR, LFT, RFT, lactate.
IE: Modified Duke Criteria — 2 major, or 1 major + 3 minor, or 5 minor. Blood cultures ×3 from different sites. TEE if prosthetic valve or TTE negative with high suspicion.
Cholangitis: TG18 — (fever/chills OR ↑inflammatory markers) + (jaundice OR abnormal liver chemistries). Definite if + biliary dilation + aetiology on imaging.
CSF interpretation: Bacterial = neutrophils, ↓glucose, ↑protein. Viral = lymphocytes, normal glucose. TB = lymphocytes, very ↓glucose, very ↑↑↑protein. Crypto = lymphocytes, Indian ink +, cryptococcal Ag +.
PBS clues: Left shift = severe infection/sepsis. Atypical lymphocytes = EBV. Blasts ≥ 20% = acute leukaemia. Schistocytes = DIC/TTP.
Key principle: Don't delay empirical antibiotics to complete the workup. Blood cultures BEFORE antibiotics → give antibiotics → then do LP/imaging.
High Yield Summary — Management of Fever/Chills
Three pillars: (1) Resuscitate, (2) Find and treat the source, (3) Supportive care.
Sepsis Hour-1 Bundle: Lactate, blood cultures BEFORE Abx, broad-spectrum IV Abx within 60 min, 30 mL/kg crystalloid if hypotension/lactate ≥ 4, vasopressors if MAP < 65 after fluids.
Vasopressor: Norepinephrine 1st line. Vasopressin or epinephrine added if needed. Dobutamine for low CO with adequate filling. Crystalloid (balanced preferred), NO starch colloids.
Empirical Abx for unknown source: Vancomycin + piperacillin-tazobactam/ceftriaxone/carbapenem. Add double anti-pseudomonal if Pseudomonas likely.
Neutropenic fever: Medical emergency. Low risk: PO cipro + augmentin. High risk: IV ceftazidime/cefepime/tazocin/carbapenem. Add vanco for MRSA, amphotericin B if no response after 5 days.
Cholangitis: Abx + biliary decompression (ERCP → PTBD → ECBD). 15% fail antibiotics alone.
Liver abscess: Abx 4–6 weeks + percutaneous drainage (< 5cm needle, > 5cm catheter). Klebsiella: meningitic-dose ceftriaxone + eye consult. Amoebic: metronidazole alone usually sufficient.
Antipyretics: Paracetamol 1st line. NSAIDs C/I in myocarditis, dengue, CKD, GI bleeding. Aspirin C/I in children (Reye) and thyroid storm (↑free T₄). Physical cooling essential in hyperthermia.
Do NOT delay Abx for investigations. Blood cultures BEFORE antibiotics → give antibiotics → then LP/imaging.
High Yield Summary — Complications of Fever/Chills
Direct complications of fever: Febrile seizures (children 6mo–5y), dehydration/electrolyte disturbance, cardiovascular stress (↑O₂ demand → ACS/AF/decompensated HF), hyperpyrexia > 41°C (protein denaturation → rhabdomyolysis → DIC → MODS), delirium (especially elderly).
Sepsis → MODS: Respiratory (ARDS), Cardiovascular (septic shock), Renal (ATN/AKI), Hepatic (jaundice/GI bleed/ileus), Neurological (septic encephalopathy/CIP), Haematological (DIC).
DIC paradox: Simultaneous thrombosis (organ damage) AND bleeding (consumption of clotting factors).
Condition-specific complications:
- Pneumonia: respiratory failure, empyema, SIADH, arrhythmia (AF)
- TB meningitis: CN palsies, hydrocephalus, infarction (endarteritis), SIADH
- Liver abscess: rupture, pleuropulmonary complications, endophthalmitis (Klebsiella)
- IE: septic emboli (stroke, organ infarction), immune complex GN, valvular destruction → HF
- Pyelonephritis: perinephric abscess, urosepsis, AKI
- Meningitis: hydrocephalus, CN palsies, seizures/epilepsy, cerebral infarction, deafness
Iatrogenic complications: Paracetamol hepatotoxicity, NSAID GI/renal, antibiotic-associated C. diff, anti-TB hepatotoxicity, fluid overload from aggressive resuscitation, vasopressor-related ischaemia, transfusion reactions.
Ear Pain/hearing
Ear pain (otalgia) and hearing impairment are symptoms arising from conditions affecting the external, middle, or inner ear—such as infections, cerumen impaction, or eustachian tube dysfunction—that disrupt normal sound conduction or auditory perception.
Foot/toe Pain
Foot or toe pain is discomfort arising from musculoskeletal, neurological, vascular, or dermatological conditions affecting the structures of the foot and toes, commonly caused by plantar fasciitis, metatarsalgia, gout, Morton's neuroma, or trauma.