What is the definition of febrile neutropenia, including the absolute neutrophil count and temperature criteria, and what is the recommended initial empiric management?

Febrile Neutropenia Definition

Febrile neutropenia is defined as a single oral temperature ≥38.3°C (101°F) or a temperature ≥38.0°C (100.4°F) sustained for ≥1 hour, occurring in a patient with an absolute neutrophil count (ANC) <500 cells/µL or expected to fall below 500 cells/µL within 48 hours. 1

Temperature Criteria

• Single oral temperature ≥38.3°C (101°F) meets the fever threshold and triggers immediate evaluation. 1
• Alternatively, a temperature ≥38.0°C (100.4°F) sustained over ≥1 hour also defines fever in this context. 1
• Axillary temperature >38.5°C for >1 hour is an older definition that has been largely superseded by the oral temperature criteria above. 2

Neutrophil Count Criteria

• ANC <500 cells/µL is the critical threshold that defines neutropenia in febrile neutropenia. 1, 3
• ANC expected to decline to <500 cells/µL within the next 48 hours also qualifies, even if the current count is higher. 1, 4
• Some sources use ANC <1,000 cells/µL with expected decline to <500 cells/µL, but the <500 cells/µL threshold is the standard for clinical decision-making. 5

Clinical Significance

• Any fever in a patient with ANC <500 cells/µL is a medical emergency requiring evaluation and treatment within 2 hours, regardless of whether the temperature reaches the full 38.3°C threshold. 1
• Profound neutropenia (ANC <100 cells/µL) carries the highest infection risk and mortality, with one study showing ANC <100 cells/µL as the only independent predictor of mortality. 5, 6
• The duration of neutropenia is equally important: anticipated neutropenia >7 days defines high-risk patients who require prophylactic antimicrobials and more intensive management. 1, 7

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Initial Empiric Management

Immediate Actions (Within 2 Hours)

• Obtain blood cultures from two separate sites: one from a peripheral vein and one from each lumen of any central venous catheter, before administering antibiotics. 1
• Collect urine culture and obtain chest radiograph as part of the initial infectious work-up. 1
• Order complete blood count, comprehensive metabolic panel, liver enzymes, coagulation panel, C-reactive protein, and lactate dehydrogenase. 1

Risk Stratification

High-risk features (require inpatient IV therapy):

• Anticipated neutropenia >7 days 1, 7
• ANC <100 cells/µL (profound neutropenia) 1, 6
• Hemodynamic instability 1
• Significant mucositis or other serious comorbidities 1
• Underlying hematologic malignancy or allogeneic stem-cell transplant 7

Low-risk features (eligible for outpatient oral therapy):

• Anticipated neutropenia <7 days 1
• MASCC score ≥21 1
• No significant comorbidities and hemodynamically stable 1

Empiric Antibiotic Therapy

High-Risk Patients (Inpatient IV)

• Start an antipseudomonal β-lactam within 2 hours: cefepime is the preferred first-line agent. 1
• Alternatives include: piperacillin-tazobactam, ceftazidime, meropenem, or imipenem. 1
• Add vancomycin only when specific indications are present: suspected catheter-related infection, hemodynamic instability, known MRSA colonization, skin/soft-tissue infection, or severe mucositis. 1
• Do not add vancomycin empirically in the absence of these risk factors, as routine use increases resistance without improving outcomes. 1

Low-Risk Patients (Outpatient Oral)

• Oral ciprofloxacin 500 mg twice daily plus amoxicillin-clavulanate is the recommended outpatient regimen for low-risk patients (MASCC ≥21). 1, 8
• Do not use fluoroquinolone empiric therapy if the patient is already receiving fluoroquinolone prophylaxis. 8
• Outpatient therapy requires reliable follow-up and the ability to return immediately if clinical deterioration occurs. 1

Supportive Care

• Initiate or continue G-CSF (filgrastim 5 µg/kg/day subcutaneously) in high-risk patients with anticipated prolonged neutropenia (>7 days), continuing until ANC ≥500 cells/µL for two consecutive days. 7
• Maintain hemoglobin ≥7 g/dL and platelet count >30 × 10⁹/L with transfusions as needed. 1
• Administer normal saline bolus 10-20 mL/kg (maximum 1,000 mL) if hypotension develops. 1

Duration of Antibiotic Therapy

• If afebrile by day 3 and ANC ≥500 cells/µL: continue antibiotics until the patient remains afebrile for ≥48 hours and ANC >500 cells/µL for two consecutive days. 1
• If afebrile but ANC remains <500 cells/µL (high-risk): continue IV antibiotics until ANC recovery. 1
• If fever persists >3-4 days: reassess for resistant organisms, fungal infection, or inadequate source control; consider adding empiric antifungal therapy (fluconazole, micafungin, or amphotericin B) if fever persists 4-7 days. 1

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Critical Pitfalls to Avoid

• Never delay antibiotics while awaiting the "classic" 38.3°C threshold or culture results in severe neutropenia; even temperatures of 38.0-38.5°C warrant immediate treatment. 1
• Do not overlook relative hypotension: establish each patient's baseline blood pressure before assuming values are normal. 1
• Never attribute fever solely to cytokine effects (e.g., from immunotherapy) without first ruling out infection. 1
• Do not stop antibiotics prematurely in persistently neutropenic patients; therapy must continue until ANC recovery even if the patient becomes afebrile. 1, 8
• Recognize that inflammatory signs may be minimal: localized pain at common infection sites (oral cavity, pharynx, esophagus, lung, perineum, catheter sites) may be the only clue to infection. 1