Neutropenic sepsis

Overview

•Neutropenic sepsis = neutrophil count <0.5 x10⁹/L (or <1.0 x10⁹/L with expected rapid fall) + any feature of sepsis

•Most commonly complicates cytotoxic chemotherapy; neutrophil nadir typically 7-14 days post-cycle

•Mortality 2-21%; Gram-negative bacteraemia and fungal infection carry highest mortality

🚨

Every hour of delay to antibiotics is associated with measurable increases in mortality. NICE mandates empirical antibiotics within 1 hour of presentation.

Presentation

•Classic signs of infection (pus, erythema, abscess) are often absent - neutrophils are required to produce them

•Fever - temperature ≥38°C (single reading)

•Hypothermia - <36°C (sinister sign of overwhelming sepsis)

•Rigors - indicates bacteraemia

•Tachycardia - HR >90 bpm

•Tachypnoea - RR >20 breaths/min

•Hypotension - SBP <90 mmHg or MAP <65 mmHg (septic shock)

•Altered mental status - confusion, agitation, reduced consciousness

•Inspect mouth (mucositis), perianal area (no DRE in neutropenia), skin, nail folds, and all vascular access sites

Investigations

⚠️

Do not delay antibiotics to obtain cultures. Draw blood cultures (peripheral + each lumen of any central line) simultaneously with or immediately before giving antibiotics.

🥇 First-line

•FBC with differential - confirms neutropenia

•Blood cultures x2 - peripheral + each lumen of central venous catheter

•Serum lactate - >2 mmol/L indicates sepsis; >4 mmol/L indicates septic shock

•U&E, LFTs - assess organ dysfunction and guide antibiotic dosing

•Urine culture, CRP, chest X-ray (consolidation may be attenuated due to absent neutrophils)

🥈 Second-line

•Coagulation screen if DIC suspected; CT chest/abdomen if no source after 48-72 h; beta-D-glucan/galactomannan if invasive fungal infection suspected (neutropenia >7 days)

Management

•All patients with suspected neutropenic sepsis in primary care must be referred immediately for emergency hospital admission - no 'watch and wait'

•First-line empirical antibiotic: piperacillin-tazobactam 4.5 g IV - must be given within 1 hour of presentation (NICE CG151)

•IV fluid resuscitation with crystalloid for haemodynamic compromise

•Risk stratify with MASCC score - score ≥21 = low risk (may be suitable for oral antibiotics and close outpatient follow-up); score <21 = high risk (inpatient IV antibiotics)

•De-escalate antibiotics once blood culture sensitivities available

Prevention

•G-CSF: filgrastim or pegfilgrastim SC - for patients at >20% risk of febrile neutropenia per cycle or after a previous episode; shortens neutrophil nadir

•Antibacterial prophylaxis: levofloxacin 500 mg oral OD during expected period of neutropenia (<0.5 x10⁹/L for >7 days)

•Antifungal prophylaxis: fluconazole for moderate risk; posaconazole for high risk (e.g. AML induction, HSCT)

•Antiviral prophylaxis: aciclovir for HSV-seropositive patients undergoing high-dose chemotherapy or stem cell transplantation

•Patient education: written and verbal information on temperature threshold (≥38°C), when to present to ED directly, and not to wait for a GP appointment

Complications

•Septic shock - MAP <65 mmHg despite fluids; requires vasopressors; mortality >40%

•AKI - hypoperfusion, nephrotoxic antibiotics (aminoglycosides), direct sepsis injury

•DIC - coagulopathy with simultaneous bleeding and thrombosis

•Invasive fungal infection - Candida or Aspergillus in prolonged neutropenia; significantly increases mortality

•Post-sepsis syndrome - fatigue, cognitive impairment, anxiety/PTSD in ~40% of survivors