Key Facts

Neutropenic sepsis is the most common oncological emergency, occurring in patients with chemotherapy-induced neutropenia. It carries significant mortality if antibiotics are delayed. Risk assessment using the MASCC score allows stratification into low and high-risk groups.

Epidemiology

• Occurs in ~15–25% of patients receiving cytotoxic chemotherapy
• Higher risk with haematological malignancies (40–50%) vs solid tumours (10–15%)
• UK incidence: ~12,000–15,000 episodes per year
• In-hospital mortality: 2–5% overall, up to 50% with Gram-negative bacteraemia
• Accounts for ~10% of cancer-related deaths

Aetiology

• Chemotherapy: most common cause — nadir typically 7–14 days after treatment
• Haematological malignancy: bone marrow infiltration
• Radiotherapy: pelvic or total body irradiation
• Drug-induced: carbimazole, clozapine, sulfasalazine
• Organisms: 60% no organism identified; Gram-positive (50–60%): coag-neg staph, S. aureus, Enterococcus; Gram-negative (30–40%): E. coli, Klebsiella, Pseudomonas; Fungi (5–10%): Candida, Aspergillus

Pathophysiology

• Cytotoxic chemotherapy destroys rapidly dividing cells including myeloid precursors in bone marrow
• Neutrophil nadir typically occurs 7–14 days post-chemotherapy
• Absent neutrophil-mediated innate immunity → inability to mount inflammatory response → atypical infection presentation
• Gut mucosal barrier breakdown (mucositis) → bacterial translocation
• Central venous catheter biofilms serve as a nidus for infection

Typical Presentation

• Fever (≥38°C) — may be the only sign in neutropenic patients
• Rigors, sweating
• Tachycardia, hypotension (late signs)
• Malaise, lethargy

Atypical Features (due to absent neutrophils)

• Absent pus formation — wound infections may not appear inflamed
• Absent infiltrates on CXR despite pneumonia
• Minimal erythema despite soft tissue infection
• Normal or low CRP despite severe infection

Site-Specific Features

• Mucositis: oral ulceration, dysphagia, odynophagia
• Line infection: erythema/tenderness at exit site, rigors on line flushing
• Perianal infection: pain, tenderness (avoid rectal examination)
• Respiratory: cough, dyspnoea (atypical organisms: PCP, CMV, Aspergillus)

Red Flags

• Neutrophils <0.1 × 10⁹/L (profound neutropenia)
• Septic shock (MAP <65 mmHg despite fluid resuscitation)
• Suspected line infection with tunnel infection/septic thrombophlebitis
• Persistent fever >48 hours on empirical antibiotics
• Perianal symptoms (risk of Gram-negative septicaemia)

Bedside

• Observations: temperature, HR, BP, RR, SpO2, urine output — calculate NEWS2
• Blood glucose: stress response, steroid use
• Urinalysis: pyuria may be absent

Bloods

• FBC: confirm neutrophil count <0.5 × 10⁹/L
• Blood cultures: minimum 2 sets (peripheral + each lumen of central line) BEFORE antibiotics
• U&Es, LFTs, CRP, lactate: assess organ function and severity
• Coagulation screen: DIC screening
• Procalcitonin: may help distinguish bacterial infection

Imaging

• CXR: baseline; note infiltrates may be absent in neutropenia
• CT chest: if persistent fever — look for fungal infection (halo sign, air crescent sign in aspergillosis)
• CT abdomen: if abdominal symptoms — typhlitis, abscess

Special Tests

• MASCC score: risk stratification (≥21 low risk, <21 high risk)
• Galactomannan and beta-D-glucan: if invasive fungal infection suspected
• CMV/EBV PCR: if viral reactivation suspected
• Stool culture and C. difficile toxin: if diarrhoea

Non-pharmacological

• Reverse barrier nursing: single room, hand hygiene, visitors screening
• IV fluid resuscitation: 500ml 0.9% NaCl bolus if hypotensive or lactate >2
• Central line assessment: inspect exit site; consider line removal if tunnel infection or persistent bacteraemia >48 hours

Pharmacological

Empirical antibiotics (within 60 minutes — NICE CG151):

• First-line: piperacillin-tazobactam 4.5g TDS IV (or meropenem 1g TDS IV if penicillin allergy or local resistance)
• Add vancomycin 15–20 mg/kg BD IV if: suspected line infection, MRSA risk, skin/soft tissue infection, haemodynamic instability
• Add gentamicin 5mg/kg OD IV if: septic shock or suspected Gram-negative sepsis

If fever persists >48 hours:

• Review cultures, consider line removal, CT imaging
• Broaden antibiotics (e.g. add meropenem if on taz, or add antifungal)

Antifungal therapy (if fever >4–7 days):

• Liposomal amphotericin B (AmBisome) 3mg/kg/day IV, or
• Caspofungin 70mg day 1 then 50mg/day IV

G-CSF (filgrastim):

• 5 mcg/kg/day SC — consider for high-risk episodes, prolonged neutropenia, septic shock
• Primary prophylaxis if regimen carries >20% risk of febrile neutropenia (NICE TA416)

Low-risk patients (MASCC ≥21):

• Oral amoxicillin-clavulanate 625mg TDS + ciprofloxacin 500mg BD — with close follow-up

Surgical/Interventional

• Central line removal: if tunnel infection, persistent bacteraemia, fungaemia
• Surgical drainage: of collections/abscesses once neutrophils recover

Referral Criteria

• Immediate oncology/haematology team involvement
• ICU referral for septic shock or multi-organ failure
• Infectious diseases for persistent fever, unusual organisms, or immunocompromised patients

• Overall mortality: 2–5% per episode
• Gram-negative bacteraemia mortality: 20–50%
• Fungal infection mortality: 30–50% (invasive aspergillosis ~50%)
• Low-risk (MASCC ≥21): mortality <5%; suitable for outpatient management
• High-risk (MASCC <21): mortality 10–20%
• Duration of neutropenia is the strongest predictor of outcome
• Mortality increases ~18% for each hour of antibiotic delay
• With prompt appropriate treatment, >90% survive an episode of febrile neutropenia

MASCC Risk Index

Empirical Antibiotic Algorithm