Febrile neutropenia

Overview

Febrile neutropenia (neutropenic sepsis) is the most common reason a cancer patient on chemotherapy comes to the emergency department. Without neutrophils, the body cannot fight bacteria and fungi, and it cannot show the usual signs of infection (pus, consolidation, meningism).

It is an oncological emergency: delay in antibiotics increases deaths. Every unwell patient within a few weeks of chemotherapy should be treated as having neutropenic sepsis until the blood count proves otherwise.

Definition

• Neutropenia: absolute neutrophil count (ANC) below 0.5 × 10⁹/L, or below 1.0 × 10⁹/L and expected to fall below 0.5 within 48 hours.
• Fever: a single oral temperature of 38.3 °C or more, or 38.0 °C or more sustained for 1 hour (IDSA definition). Some UK sources use 38.5 °C once or 38.0 °C for an hour.
• Profound neutropenia: ANC below 0.1 × 10⁹/L.

Causes of neutropenia

Organisms

• Gram-negative bacilli (from the gut): E. coli, Klebsiella, Pseudomonas aeruginosa. They cause the most rapid deaths.
• Gram-positive cocci: coagulase-negative staphylococci and Staph. aureus (indwelling lines), viridans streptococci (mucositis), enterococci. Now the most frequently isolated group.
• Fungi (with prolonged neutropenia, usually beyond 7–10 days): Candida and Aspergillus; mucormycosis less often.
• Viruses: HSV, VZV, CMV, respiratory viruses.

Differential diagnosis of fever in a neutropenic patient

• Infection (most important): bacteraemia, central line infection, pneumonia, UTI, skin and perianal infection, mucositis, neutropenic enterocolitis, fungal infection, viral reactivation.
• Non-infective: blood product transfusion reaction, drug fever (e.g. cytarabine, bleomycin), tumour fever (lymphoma), thrombosis/PE, GVHD after stem cell transplant.

Always assume infection first.

Assessment

• ABCDE and sepsis screen: pulse, BP, respiratory rate, oxygen saturation, consciousness, urine output, lactate.
• History: date of last chemotherapy, type of cancer, lines, recent antibiotics, previous resistant organisms.
• Examine carefully: mouth (mucositis), chest, abdomen, line exit sites, skin, perianal area.
• Do not perform a digital rectal examination or give rectal medicines (risk of bacteraemia).

Investigations (do not delay antibiotics for them)

• Blood cultures: one peripheral set and one from each lumen of any central line.
• FBC with differential, U&E, LFTs, CRP, lactate, coagulation.
• Urine culture; sputum, stool, wound or throat swabs as indicated.
• Chest X-ray.

• Later, if fever persists: CT chest (fungal nodules with halo sign), serum galactomannan (Aspergillus), beta-D-glucan, CT abdomen.

Risk stratification

• The MASCC score (Multinational Association for Supportive Care in Cancer) adds points for mild symptoms, no hypotension, no COPD, solid tumour or no previous fungal infection, no dehydration, outpatient status and age under 60.
• Score 21 or more = low risk.

Management

1. Antibiotics within 1 hour

• Monotherapy with an antipseudomonal beta-lactam:
  • Piperacillin-tazobactam (commonly first line), or
  • Meropenem (or another carbapenem; preferred if ESBL organisms are likely), or
  • Cefepime / ceftazidime.
• Add an aminoglycoside (gentamicin or amikacin) in shock or where resistance is common.
• Penicillin allergy: use a regimen such as aztreonam or meropenem plus vancomycin according to local policy.

2. When to add Gram-positive cover (vancomycin or teicoplanin)

• Suspected central line infection (redness, pus at the exit site, rigors on flushing)
• Skin or soft-tissue infection
• Known MRSA colonisation
• Pneumonia, haemodynamic instability or Gram-positive cocci in blood culture

3. Supportive care

• IV fluids, oxygen, early critical care referral and vasopressors for septic shock.
• Remove an infected central line if there is tunnel infection, persistent bacteraemia, Staph. aureus, Pseudomonas or Candida.
• G-CSF (granulocyte colony-stimulating factor; for example filgrastim) is given mainly for prevention after chemotherapy with high neutropenia risk, and in selected high-risk patients; its common side-effect is bone pain.

4. Review at 48–72 hours

• Fever settles, cultures negative: continue until stable; switch to oral or stop according to policy, usually when ANC is recovering.
• Organism found: tailor antibiotics to sensitivities.
• Still febrile but stable: usually do not change antibiotics just for fever; re-examine and repeat cultures.
• Clinical deterioration: broaden cover (e.g. switch to meropenem, add vancomycin or amikacin).

5. Persistent fever after 4–7 days of antibiotics

• Suspect invasive fungal infection.
• CT chest: nodules, halo sign, later air-crescent sign in invasive aspergillosis.
• Serum galactomannan supports aspergillosis.
• Start an antifungal: voriconazole (aspergillosis; causes visual disturbance, photosensitivity), liposomal amphotericin B, or an echinocandin (caspofungin) for Candida.

Special situations

Neutropenic enterocolitis (typhlitis)

• Inflammation and necrosis of the bowel wall, mostly the caecum, during profound neutropenia (often in leukaemia treatment).
• Fever, right iliac fossa pain, diarrhoea, distension.
• CT shows caecal wall thickening.
• Treat with bowel rest, IV fluids and broad-spectrum antibiotics covering Gram-negatives and anaerobes (e.g. piperacillin-tazobactam or meropenem); surgery for perforation.

Mucositis

• Damaged mouth and gut lining lets viridans streptococci and gut organisms into the blood; HSV reactivation is common.

Prevention

• Hand hygiene, careful line care, isolation for profound neutropenia.
• Food hygiene ("neutropenic diet": avoid raw meat, unpasteurised dairy, unwashed salads).
• G-CSF after high-risk chemotherapy.
• Prophylactic fluoroquinolone (levofloxacin or ciprofloxacin) for expected profound neutropenia lasting more than 7 days; antifungal prophylaxis (posaconazole or fluconazole) in high-risk haematology patients.
• Patient education: a 24-hour contact number and the rule to attend at once with fever.

Quick revision

• Fever + ANC below 0.5 × 10⁹/L = emergency.
• ANC = WBC × (% neutrophils + % bands).
• Nadir 7–14 days after chemotherapy.
• Blood cultures (peripheral + each line lumen), then antibiotics within 1 hour.
• Piperacillin-tazobactam or meropenem; add vancomycin for lines, skin, MRSA, shock.
• MASCC 21 or more = low risk; oral ciprofloxacin + co-amoxiclav possible.
• Fever beyond 4–7 days → think fungus: CT, galactomannan, voriconazole or amphotericin.
• Typhlitis = caecum; avoid rectal examination.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Levinson's Review of Medical Microbiology and Immunology).

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