Febrile neutropenia

Definition

Febrile neutropenia is fever with a markedly reduced neutrophil count, usually resulting from myelosuppressive cytotoxic drugs or bone marrow infiltration by hematologic neoplasms. It is regarded as an oncologic emergency.

• Definition according to IDSA, ASCO, and NCCN: oral temperature ≥ 38.3 °C once or sustained ≥ 38.0 °C over 1 hour and absolute neutrophil count < 0.5 × 10⁹/L or an expected decrease to < 0.5 × 10⁹/L within 48 hours.
• ESMO: sustained temperature > 38.0 °C over 2 hours.
• NICE (neutropenic sepsis): neutrophils ≤ 0.5 × 10⁹/L and temperature > 38 °C or other signs of clinically significant sepsis.

Severity of neutropenia: mild 1,000–1,500/µL, moderate 500–1,000/µL, severe < 500/µL; below 200/µL the term agranulocytosis is used.

Clinical features

• Fever is often the only sign of infection.
• In severe neutropenia, typical signs of inflammation (redness, swelling, pain, infiltrates) are absent or only faint; below 200/µL, leukocytosis and pyuria may not occur.
• Local findings such as oral ulcers, stomatitis, or pharyngitis are often subtle.
• Common sites of infection: lung, bloodstream (bacteremia), skin and catheter exit sites, oral cavity, perianal region.
• Blood cultures show gram-positive and gram-negative organizms about equally often; in about half of patients, no pathogen and no focus can be found despite diagnostic work-up (fever of unknown origin).
• Risk of rapid progression to sepsis and septic shock; with prolonged neutropenia, increasingly invasive fungal infections.

Diagnosis

• Complete blood count with differential to determine the absolute neutrophil count.
• Thorough physical examination, repeated: skin and mucosa (including herpetic lesions), catheter exit sites, sinuses, ears, perianal region, fundus.
• Blood cultures: at least two sets from separate venipunctures, with an indwelling central venous catheter additionally from the catheter.
• Further cultures: urine; stool with diarrhea (including Clostridioides difficile); swabs of mucosal ulcers; material from skin lesions.
• Inflammatory markers: procalcitonin predicts bacteremia better than CRP; measured serially, they help detect complications early.
• Imaging: the conventional chest x-ray has low sensitivity in neutropenia; low-exposure chest CT in case of respiratory symptoms or suspected invasive aspergillosis; serum galactomannan and 1,3-beta-D-glucan.
• Risk assessment: the MASCC score estimates the risk of a complicated course (high risk < 21 points); the CISNE score is used in apparently stable patients. An expected duration of neutropenia of more than 7 days is considered high risk.

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Further reading (open access)

1. MSD Manual Professional: Neutropenia
2. AGIHO-Leitlinie 2024: Fever of unknown origin in adult neutropenic patients (Lancet Reg Health Eur, PMC-Volltext)

Cross-references