Management of Neutropenia

Severity Classification and Risk Stratification

Neutropenia severity is classified by absolute neutrophil count (ANC): mild (1.0–1.5 × 10⁹/L), moderate (0.5–1.0 × 10⁹/L), and severe (<0.5 × 10⁹/L), with the critical threshold of ANC <500 cells/µL triggering prophylactic antimicrobial therapy in high-risk patients. 1

Fever Definition

Fever 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 2
Febrile neutropenia (ANC <500 cells/µL plus fever) constitutes a medical emergency requiring empiric antibiotics within 2 hours 2, 1

High-Risk Features (Require Inpatient Management)

Anticipated prolonged neutropenia >7 days 2, 1
Profound neutropenia (ANC <100 cells/µL) 1
Underlying hematologic malignancy or allogeneic stem-cell transplantation 2, 1
Hemodynamic instability or septic shock 2
Significant mucositis or organ dysfunction 2

Low-Risk Features (Eligible for Outpatient Management)

Expected brief neutropenia <7 days 2
MASCC score ≥21 2
Solid tumor malignancy (non-hematologic) 2
Hemodynamically stable with adequate oral intake 2

Management of Febrile Neutropenia

High-Risk Patients (Inpatient IV Therapy)

Initiate IV antipseudomonal β-lactam within 2 hours of fever onset; cefepime 2g every 8 hours is the preferred first-line agent. 2

Initial Empiric Regimen

Preferred: Cefepime 2g IV every 8 hours 2
Alternatives: Meropenem, imipenem, piperacillin-tazobactam, or ceftazidime 2
Add vancomycin ONLY when: suspected catheter-related infection, hemodynamic instability, known MRSA colonization, skin/soft-tissue infection, or severe mucositis 2

Diagnostic Workup (Before Antibiotics)

Two sets of blood cultures from separate sites (peripheral and any central line) 2
Urine culture only if urinary symptoms present 2
Chest radiograph if respiratory symptoms, hypoxia, or tachypnea 2
Cultures from any suspected infection site 2

Duration of Therapy

Continue antibiotics until ANC >500 cells/µL for ≥2 consecutive days and patient afebrile for ≥48 hours 2
For documented infections, continue appropriate antibiotics for at least the duration of neutropenia (until ANC >500 cells/µL) or longer if clinically necessary 2

Persistent Fever (4–7 Days)

Add empiric antifungal therapy (voriconazole or liposomal amphotericin B) 2
Obtain chest CT to evaluate for invasive fungal infection 2
Reassess for resistant organisms (MRSA, VRE, ESBL, KPC) and non-infectious causes 2

Low-Risk Patients (Outpatient Oral Therapy)

Low-risk febrile neutropenic patients (MASCC ≥21) may receive outpatient oral therapy with ciprofloxacin 500mg twice daily plus amoxicillin-clavulanate, provided reliable follow-up is ensured. 2

Eligibility Criteria (ALL Must Be Met)

MASCC score ≥21 2
Hemodynamically stable without organ dysfunction 2
Adequate oral intake with reliable follow-up 2
No pneumonia, indwelling catheter, or severe soft-tissue infection 2

Oral Regimen

Preferred: Ciprofloxacin 500mg PO twice daily + amoxicillin-clavulanate 875mg PO twice daily 2
Alternative: Levofloxacin 750mg PO daily 2
Do NOT use fluoroquinolone if patient already receiving fluoroquinolone prophylaxis 2

Management of Afebrile Neutropenia

High-Risk Afebrile Patients (Expected Neutropenia >7 Days)

Fluoroquinolone prophylaxis (levofloxacin 500mg daily) should be initiated immediately in high-risk afebrile patients with ANC <500 cells/µL and expected prolonged neutropenia >7 days. 2, 1

Antibacterial Prophylaxis

Levofloxacin 500mg PO daily (preferred, especially with mucositis risk) 2, 1
Ciprofloxacin 500mg PO daily (acceptable alternative) 2, 1
Continue until ANC >500 cells/µL 2, 1

Additional Prophylaxis (Per NCCN Guidelines)

Antifungal: Fluconazole 400mg PO daily starting at anticipated nadir; stop when ANC >1000 cells/µL 2, 1
PCP prophylaxis: Trimethoprim-sulfamethoxazole (double-strength) three times weekly; continue ≥6 months or until CD4 >200 cells/mm³ 2, 1
Antiviral: Acyclovir 400mg or valacyclovir 500mg PO twice daily; continue ≥6 months or until lymphocyte recovery 2, 1

Monitoring

Temperature checks every 4–6 hours 1
Daily complete blood count with differential 1
Educate patients to seek immediate care at first sign of fever 2, 1

Low-Risk Afebrile Patients (Expected Neutropenia <7 Days)

Routine antibacterial prophylaxis is NOT recommended for low-risk patients with expected brief neutropenia, as it increases antimicrobial resistance without improving clinical outcomes. 2, 1

Monitor temperature regularly and assess ANC 2, 1
Patient education on fever recognition and urgent care instructions 2, 1

Use of Granulocyte Colony-Stimulating Factor (G-CSF)

Indications

G-CSF is NOT routinely recommended for uncomplicated febrile neutropenia or afebrile neutropenia; it should be reserved for high-risk patients with expected prolonged neutropenia >7 days or specific high-risk conditions. 2

Consider G-CSF when: pneumonia, hypotensive episodes, severe cellulitis or sinusitis, systemic fungal infections, multiorgan dysfunction secondary to sepsis, or documented infections not responding to appropriate antimicrobial therapy 2
Filgrastim 5µg/kg/day subcutaneously starting 24–72 hours after chemotherapy; continue until ANC >500 cells/µL for two consecutive days 2, 1

Contraindications

Active chest radiotherapy (associated with increased mortality) 2, 1
Active sepsis 1

Evidence Limitations

G-CSF consistently shortens duration of neutropenia but has NOT consistently reduced febrile morbidity, duration of fever, use of anti-infectives, costs, or infection-related mortality 2
ASCO guidelines recommend against routine use in uncomplicated fever and neutropenia 2

Infection Prevention Measures

Environmental Precautions

Implement neutropenic precautions when ANC <500 cells/µL and expected duration >7 days 1
Strict hand hygiene for all healthcare workers and visitors 1
Avoid fresh flowers, plants, and uncooked foods 1

Supportive Care

Transfuse platelets when count <30,000/mm³ 1
Transfuse packed red blood cells when hemoglobin <7.0 g/dL 1
Use only irradiated blood products in severely immunocompromised patients 1

Follow-Up Monitoring

During Neutropenia (ANC <500 cells/µL)

Daily CBC with differential 1
Temperature monitoring every 4–6 hours 1
Clinical assessment for new infection signs 2

After Initial Episode

For mild neutropenia (ANC 1.0–1.5 × 10⁹/L) in asymptomatic patients, repeat CBC with differential in 2–4 weeks to establish whether transient or chronic 1
Weekly CBC monitoring for first 4–6 weeks if on treatments affecting neutrophil counts 1

Chronic Neutropenia (>3 Months)

Consider bone marrow aspiration and biopsy with cytogenetic analysis when: persistent neutropenia >3 months despite normal initial workup, concurrent bi- or pancytopenia, peripheral smear showing dysplastic changes or blasts, or clinical suspicion of inherited neutropenia 1

Critical Pitfalls to Avoid

Do NOT delay empiric antibiotics beyond 2 hours in febrile neutropenia while awaiting culture results 2, 1
Do NOT withhold antibacterial prophylaxis in high-risk afebrile patients with expected neutropenia >7 days 2, 1
Do NOT discontinue antibiotics prematurely in persistently neutropenic patients; therapy must continue until ANC recovery 2
Do NOT add vancomycin empirically without specific high-risk indications (catheter infection, MRSA colonization, hemodynamic instability) 2
Do NOT use fluoroquinolone empiric therapy in patients already receiving fluoroquinolone prophylaxis 2
Do NOT use G-CSF during active chest radiotherapy due to increased mortality risk 2, 1
Do NOT obtain blood cultures in afebrile, clinically stable patients with leukopenia, as yield is low 1

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