Febrile Neutropenia

Febrile Neutropenia: Quick Recap Table for Management

Aspect	Key Points
Definition	Fever (≥38.3°C once or ≥38.0°C for >1hr) + Neutropenia (ANC <500/µL or <1000/µL with predicted decline)
Etiology	Chemotherapy, Bone Marrow Disorders, Medications, Radiation
Risk Factors	Prolonged/Severe Neutropenia, Mucositis, Catheters, Comorbidities, Corticosteroids
Assessment	Thorough history & physical exam focusing on infection sources
Investigations	CBC, Blood Cultures, UA/UC, CXR (+/- additional tests based on suspicion)
Risk Stratification	High, Intermediate, and Low Risk based on patient and clinical factors
Management	1. Empiric Antibiotics (within 6 hours) 2. Supportive Care (G-CSF, hydration, transfusions) 3. Consider Antifungals if high risk & persistent fever 4. Monitor closely & adjust treatment based on clinical response
Antibiotic Choice	Monotherapy or Duotherapy depending on risk and suspected pathogens
Antifungal Choice	Amphotericin B, Voriconazole, Posaconazole, Caspofungin
Outpatient Management	Possible for Low Risk patients with close monitoring
Key Principle	Early recognition and aggressive management are crucial to improving outcomes

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Definition

Febrile neutropenia is characterized by:

• Fever:

  • Oral temperature ≥ 38.3°C (101°F) at least once, OR

  • Oral temperature ≥ 38.0°C (100.4°F) for more than one hour.

• Neutropenia:

  • Absolute neutrophil count (ANC) < 500/μL, OR

  • ANC < 1,000/μL with a predicted decline to < 500/μL.

Etiology

1. Bone Marrow Disorders:

   • Aplastic anemia

   • Leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia)

   • Multiple myeloma

   • Myelodysplastic syndrome (MDS)

   • Lymphoma involving bone marrow

   • Infection- or lymphoma-associated hemophagocytic syndrome

   • Autoimmune diseases like autoimmune neutropenia

2. Medications:

   • Chemotherapy drugs (e.g., anthracyclines, cytarabine, platinum-based regimens, high-dose ifosfamide)

   • Antibiotics, NSAIDs, anti-tuberculosis drugs (e.g., isoniazid, rifampicin, pyrazinamide)

   • Immunosuppressants (e.g., azathioprine)

3. Radiation Therapy:

   • High-dose radiation, especially in the abdominal region
     

Risk Factors for Infection in Neutropenic Patients

1. Chemotherapy Regimen:

   • Intensity and duration of myelosuppression vary among regimens.

   • Regimens for acute myeloid leukemia and relapsed/refractory non-Hodgkin's lymphoma induce severe and prolonged neutropenia.

   • Newer agents like fludarabine and alemtuzumab cause immunosuppression requiring PCP and viral prophylaxis.

2. Neutrophil Count and Duration:

   • Risk of infection increases with decreasing ANC (<500-1,000/μL: 14%; <100/μL: significantly higher).

   • Prolonged neutropenia (>10 days) greatly increases infection risk.

3. Mucositis:

   • Chemotherapy or radiation-induced mucositis disrupts mucosal barriers, facilitating bacterial colonization and infection.

4. Catheters and Other Devices:

   • Presence of catheters or implanted devices elevates infection risk.

5. Comorbidities:

   • Conditions like diabetes, chronic kidney disease, systemic lupus erythematosus (SLE), and malnutrition increase susceptibility.

6. Corticosteroid Use:

   • Can mask symptoms of infection, delaying diagnosis and increasing infection risk.
     

History and Physical Examination

• History: Include exposure to contagious illnesses, recent wounds, sinus pain, surgical history, menstrual history, etc.

• Physical Examination: Focus on the oral cavity, skin (especially groin), and perianal area. Perform per rectal examination with sterile technique if needed.
  

Laboratory Investigations

1. Essential Tests:

   • Complete Blood Count (CBC)

   • Blood cultures (from peripheral blood and catheters if present)

   • Urine analysis (UA) and culture

   • Chest X-ray

2. Additional Tests (Based on Clinical Suspicion):

   • Stool examination and culture (if diarrhea is present)

   • Sputum/pus gram stain, culture, AFB staining, TB culture

   • Fungal culture, sinus X-ray, brain imaging (CT/MRI), lumbar puncture for CSF analysis

   • Abdominal imaging (ultrasound, CT)

   • Liver function tests (LFTs), renal function tests (BUN/Cr)
     

Diagnosing Invasive Aspergillosis

1. Non-Invasive Investigations:

   • Chest X-ray: Limited sensitivity for early detection.

   • Chest/Abdominal CT Scan: More sensitive for early detection (halo sign, macronodules).

   • Galactomannan Antigen Test: Non-invasive, early detection method (GMI ≥ 0.5).

   • Molecular Testing (PCR): High sensitivity but lacks standardization.

2. Invasive Investigations:

   • Tissue biopsy for histopathological examination and fungal culture.

   • Bronchoscopy and biopsy (higher risk in hematological malignancies).
     

Infections in Febrile Neutropenia

1. Bacterial Infections:

   • Susceptible to gram-positive, gram-negative, and anaerobic bacteria.

   • Blood cultures are positive in only 20-30% of cases, necessitating empirical antibiotic therapy.

2. Fungal Infections:

   • Common in hematological malignancies, with Candida and Aspergillus species being prevalent.

   • Risk factors include mucositis, broad-spectrum antibiotics, immunosuppression, catheters, and malnutrition.

   • Candida infections often present as oropharyngeal mucositis, esophagitis, or disseminated disease.

   • Aspergillus infections often involve the lungs, and sinuses, and can disseminate to the brain, liver, and spleen.

3. Viral Infections:

   • Herpesviruses, respiratory viruses, and others are common.
     

Management

1. Risk Stratification:

   • High-Risk: ANC < 100/μL, prolonged neutropenia, hematological malignancy, allogeneic stem cell transplantation, significant comorbidities, hemodynamic instability, complex infections.

   • Intermediate-Risk: Solid tumors with intensive chemotherapy, moderate neutropenia, minimal comorbidities, hemodynamically stable.

   • Low-Risk: Solid tumors with conventional chemotherapy, no comorbidities, short neutropenia, hemodynamically stable, simple infections.

2. Antibiotic Therapy:

   • Initiate within 6 hours of fever onset.

   • Empiric therapy options based on risk stratification:

   • Monotherapy: Anti-pseudomonal penicillin + β-lactamase inhibitor (piperacillin/tazobactam), carbapenem (imipenem, meropenem), fluoroquinolone (levofloxacin), cephalosporin (cefepime).

   • Duotherapy: Anti-pseudomonal cephalosporin + aminoglycoside, fluoroquinolone + aminoglycoside.

   • Vancomycin: Consider adding for catheter infections, suspected MRSA, enterococcal infection.

   • Treatment duration: 5-7 days for uncomplicated cases, 14 days for bacteremia, until ANC recovery and clinical resolution for fungal infections.

3. Catheter Removal:

   • Not routinely required for S. aureus or coagulase-negative staphylococci infections.

   • Necessary for infections with Bacillus species, C. jeikeium, P. aeruginosa, Stenotrophomonas maltophilia, Acinetobacter species, Candida species, and atypical mycobacteria.

4. Antifungal Therapy:

   • Consider empiric antifungal therapy in high-risk patients with persistent fever after 4-7 days of broad-spectrum antibiotics.

   • Amphotericin B, voriconazole, caspofungin, and intravenous itraconazole are mainstays.

   • Serial serum GM testing to guide therapy.

5. Supportive Care:

   • Granulocyte Colony-Stimulating Factor (G-CSF): Recommended for patients with chemotherapy-induced FN to shorten neutropenia duration.

   • Blood Chemistry Monitoring: Correct electrolyte imbalances, monitor renal and liver function.

   • Hydration: Maintain adequate hydration.

   • Blood Product Transfusions: Maintain Hb > 8.5 g/dL, platelet count > 10,000-20,000/μL.

6. Primary Prophylaxis with G-CSF:

   • Consider for patients with non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphoblastic leukemia, and those receiving myelosuppressive chemotherapy regimens.

7. Outpatient Management:

   • Possible for low-risk patients with appropriate home support and close follow-up.

   • Typical regimens include quinolones with or without amoxicillin/clavulanate.
     

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Conclusion

Febrile neutropenia is a serious complication requiring prompt recognition, risk stratification, and initiation of appropriate empiric antimicrobial therapy alongside supportive care to optimize outcomes. This guide provides physicians with the necessary knowledge and tools to effectively manage this condition.