Febrile Neutropenia: Succinct Guide

Febrile Neutropenia Definition

Febrile neutropenia (FN) is a medical emergency characterized by the development of fever in a patient with significant neutropenia. It is commonly seen in immunocompromised individuals, particularly those undergoing chemotherapy for malignancies.

Diagnostic Criteria

Febrile neutropenia is defined by the following criteria:

• Fever: A single oral temperature ≥ 38.3°C (101°F) or a sustained temperature ≥ 38.0°C (100.4°F) for more than 1 hour.

• Neutropenia: An absolute neutrophil count (ANC) < 500 cells/μL, or expected to fall below 500 cells/μL within 48 hours.

Etiology and Major Causes

The primary cause of febrile neutropenia is chemotherapy-induced myelosuppression. Other causes include:

• Hematological malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes)

• Bone marrow suppression due to radiation therapy

• Aplastic anemia and other bone marrow disorders

• Infections: Bacterial (Gram-negative and Gram-positive), fungal, and viral infections

• Drug-induced bone marrow suppression (e.g., immunosuppressive agents)

• Nutritional deficiencies: Vitamin B12 or folate deficiency

Common Pathogens in Febrile Neutropenia

• Gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa

• Gram-positive bacteria: Staphylococcus aureus (including MRSA), Streptococcus spp., Enterococcus

• Fungi (in prolonged neutropenia): Candida spp., Aspergillus spp.

• Viruses: Herpes simplex virus (HSV), cytomegalovirus (CMV), respiratory viruses

CISNE Score (Clinical Index of Stable Febrile Neutropenia)

The CISNE score is used to stratify the risk of complications in stable patients with Febrile Neutropenia.

Scoring Criteria

Clinical Parameter	Points
Eastern Cooperative Oncology Group (ECOG) performance status ≥2	2
Chronic obstructive pulmonary disease (COPD)	1
Cardiovascular disease	1
Mucositis (grade ≥2)	1
Monocytes <200 cells/μL	1
Stress-induced hyperglycemia	1

• Low Risk (0 points): Outpatient management may be considered.

• Intermediate Risk (1-2 points): Requires close monitoring.

• High Risk (≥3 points): Inpatient admission and aggressive treatment are recommended.

MASCC Score (Multinational Association for Supportive Care in Cancer Score)

The MASCC score helps identify low-risk patients who may be candidates for outpatient management.

Scoring Criteria

Clinical Factor	Points
No hypotension (SBP ≥ 90 mmHg)	5
No chronic obstructive pulmonary disease (COPD)	4
No dehydration requiring IV fluids	3
Mild or no symptoms	5
Solid tumor or no previous fungal infection	4
Outpatient status at fever onset	3
Age < 60 years	2

• Score ≥ 21: Low risk, may consider outpatient treatment.

• Score < 21: High risk, requires inpatient management.

Treatment and Management

Initial Evaluation and Workup

• Complete blood count (CBC) with differential

• Blood cultures (2 sets, including at least one from a central venous catheter, if present)

• Urinalysis and urine culture

• Chest X-ray or CT scan if pulmonary symptoms present

• Serum creatinine, electrolytes, and liver function tests

Empirical Antibiotic Therapy

Empirical broad-spectrum antibiotics should be initiated within 60 minutes of presentation, even before culture results are available.

Low-Risk Patients (MASCC ≥21)

• Oral therapy (if tolerating oral intake and clinically stable):

  • Amoxicillin-clavulanate + Ciprofloxacin (preferred)

  • Levofloxacin monotherapy (alternative)

High-Risk Patients (MASCC <21)

• IV therapy (requires hospitalization):

  • Monotherapy options:

    • Piperacillin-tazobactam

    • Cefepime

    • Meropenem or Imipenem (for suspected resistant infections)

  • Add Vancomycin if:

    • Suspected catheter-related infection

    • Severe mucositis with suspected Streptococcus viridans

    • Hemodynamic instability

    • Known MRSA colonization or infection

Antifungal and Antiviral Therapy

• Consider antifungal therapy (e.g., caspofungin, voriconazole) in persistent fever after 4-7 days despite broad-spectrum antibiotics.

• Antiviral therapy (e.g., acyclovir) is indicated for suspected viral reactivations (e.g., HSV, CMV in transplant patients).

Colony-Stimulating Factors (CSFs)

• Filgrastim (G-CSF) or Pegfilgrastim may be used for:

  • Severe neutropenia (ANC <100 cells/μL)

  • Expected prolonged neutropenia (>10 days)

  • Sepsis or invasive fungal infections

  • High-risk patients (e.g., elderly, multiple comorbidities)

Supportive Care

• Fluid resuscitation and electrolyte correction

• Fever control: Acetaminophen (avoid NSAIDs due to thrombocytopenia risk)

• Strict infection control: Hand hygiene, isolation precautions in neutropenic patients

Duration of Therapy

• Minimum 7 days of antibiotics or until ANC ≥1000 cells/μL and fever resolution.

• De-escalation based on culture results and clinical response.

Conclusion

Febrile neutropenia is a medical emergency requiring immediate empiric antibiotics and risk stratification using CISNE and MASCC scores. Timely management, infection control measures, and supportive care significantly reduce morbidity and mortality. Physicians should remain vigilant for complications such as sepsis, invasive fungal infections, and drug-resistant pathogens, ensuring a prompt and effective response.