Neutropenic fever

• Fever: Single oral temperature $\ge$ 38.3°C (101°F) OR $\ge$ 38.0°C (100.4°F) sustained for > 1 hour.
• Neutropenia: Absolute Neutrophil Count (ANC) < 500 cells/mm³ OR expected to decrease to < 500 within 48 hours.
• Medical Emergency: High risk of rapid progression to sepsis due to impaired inflammatory response.

Epidemiology

• Risk Factors:
  • Cytotoxic chemotherapy (nadir typically 7-10 days post-treatment).
  • Hematologic malignancies (e.g., AML, ALL), HSCT, bone marrow failure.
  • Mucosal barrier breakdown (chemo-induced mucositis).

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Etiology

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Pathophysiology

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• Pathophysiology: Cytotoxic chemotherapy $\to$ mucositis (GI tract barrier breakdown) $\to$ translocation of endogenous flora into bloodstream.
• Bacterial pathogens:
  • Gram-positives (Most Common): Staph epidermidis (coag-negative staph), Staph aureus, Streptococcus viridans, Enterococcus. often catheter-related.
  • Gram-negatives (Most Serious): Pseudomonas aeruginosa, E. coli, Klebsiella. Pseudomonas is the primary target for empiric therapy due to high mortality.
• Fungal pathogens: Candida, Aspergillus. Usually a concern in prolonged neutropenia (> 7 days).

Clinical features

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• Blunted Inflammatory Response: Fever is frequently the only sign of severe infection (absence of pus, minimal local erythema/induration).
• High-Yield Examination Focus:
  • Indwelling CVC / IV sites (erythema, tenderness).
  • Oropharynx (mucositis, thrush, dental infection).
  • Perianal region (visual inspection ONLY).
  • Lungs (crackles, tachypnea) and Skin (ecthyma gangrenosum secondary to Pseudomonas).
• CONTRAINDICATION: Avoid Digital Rectal Exam (DRE) or rectal temp due to risk of mucosal tear and bacterial translocation.

Diagnostics

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• Initial/Diagnostic Criteria:
  • Temp $\ge 38.3^{\circ }\text{C}$ + ANC $<500/\mu \text{L}$ ($\text{ANC}=\text{WBC}\times [\%\text{segs}+\%\text{bands}]$).
• Key Workup (Perform immediately before Abx, but DO NOT delay Abx administration):
  • Blood Cultures: 2 sets simultaneously (1 peripheral + 1 from each CVC lumen; or 2 peripheral if no line).
  • Labs: CBC w/ diff, CMP, LFTs, Serum lactate.
  • Targeted Cultures: Urine culture, sputum culture (if symptomatic), C. diff stool PCR (if diarrhea).
• Imaging:
  • CXR: Evaluate for pulmonary infiltrates (may present with minimal findings early due to lack of neutrophils).
  • Chest CT (High-Resolution): Indicated if pulmonary sx persist or high suspicion for fungal infection (e.g., halo sign in Invasive Aspergillosis).

Treatment

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• Immediate Action: Administer empiric broad-spectrum IV Abx within 1 hour of presentation.
• First-Line Monotherapy (Must cover Pseudomonas aeruginosa): c
  • Cefepime IV OR
  • Piperacillin-Tazobactam (Zosyn) IV OR
  • Meropenem / Imipenem-Cilastatin IV.
• Indications to add IV Vancomycin (Gram-positive coverage):
  • Hemodynamic instability / Septic shock.
  • CVC-related infection (catheter site erythema/purulence).
  • Known MRSA colonization.
  • Severe mucositis.
  • Blood culture positive for Gram-positive cocci prior to ID.
• Persistent Fever ($\ge 4-7$ Days despite broad-spectrum Abx):
  • Add Empiric Antifungal Agent: Voriconazole, Isavuconazole, Caspofungin, or Liposomal Amphotericin B.
• G-CSF (Filgrastim):
  • NOT routinely recommended for treatment of uncomplicated NF.
  • Reserved for high-risk patients with severe complications (e.g., septic shock, fungal infection, prolonged ANC $<100$).