Neutropenic Fever

Fever during chemotherapy-induced neutropenia may be the earliest sign of infection and should be taken seriously since immunosuppressed patients may not exhibit the typical inflammatory signs of infection.

Neutropenic fever is defined as:

• single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained for ≥1 hour

• and absolute neutrophil count (ANC) <500 cells/mm³ (or anticipated to decrease to <500 cells/mm³ in the next 48 hours)
  
  

Risk Stratification

An infectious etiology underlying neutropenic fever is identified in only 40-50% of patients. However, most patients presenting with neutropenic fever should be hospitalized to receive empiric antibiotic therapy. Rarely, low-risk patients with anticipated brief duration (<7 days) of neutropenia and minimal comorbid conditions can be treated as outpatients with oral antibiotic therapy and close follow-up. The Multinational Association for Supportive Care in Cancer (MASCC) Risk-Index score may be used to stratify the risk of complications in patients with neutropenic fever (a score <21 is considered high risk; see risk index score below and here).

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

Diagnostic Workup

Patients presenting with febrile neutropenia should undergo a detailed history and physical examination.

†Indications to add vancomycin include hemodynamic instability, skin or catheter site infection, concern for methicillin-resistant Staphylococcus aureus pneumonia, and blood cultures with gram-positive bacteria before final identification and susceptibilities. Abbreviations: ANC, absolute neutrophil count; ESBL, extended-spectrum b-lactamase; HCT, hematopoietic cell transplantation; IV, intravenous; MASCC, Multinational Association for Supportive Care in Cancer. (Source: Optimal Management of Neutropenic Fever in Patients with Cancer. J Oncol Pract 2019.)

Initial evaluation includes the following:

• complete history and physical are crucial to identify a focus of infection

• laboratory tests: complete blood count with differential, electrolytes, creatinine, blood urea nitrogen, liver function tests, and lactate

• routine blood cultures: at least two sets, if the patient has a central venous catheter, one set from the catheter and one peripheral

• urinalysis and urine culture

• chest radiograph: in patients with respiratory signs or symptoms

• symptom-directed workup: cultures from any other sites of suspected infection (e.g., cerebrospinal fluid, wounds, lower respiratory tract) and/or imaging (e.g., abdominal and pelvic CT in patients with GI symptoms)

• viral nasopharyngeal swabs: in patients presenting with flu-like illness
  
  

Management

Antibiotic treatment:

• Low-risk patients with febrile neutropenia should receive initial doses of empirical antibacterial therapy within 1 hour of triage and monitored for ≥4 hours before discharge. An oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if allergy to penicillin) is recommended as empirical outpatient therapy, unless fluoroquinolone prophylaxis was used before fever developed. Patients who do not defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen should be reevaluated and considered as candidates for inpatient treatment.

• High-risk patients should be started on empiric antipseudomonal monotherapy with either cefepime or ceftazidime, or if allergic, a carbapenem or piperacillin-tazobactam (algorithm varies by institutional standards and local resistance patterns).

• Other antibiotics may be added for specific complications or known/suspected antimicrobial resistance.

• Vancomycin is generally not administered empirically except in special circumstances (including suspected catheter-related infection, pneumonia, hemodynamic instability, or skin or soft tissue infection). If vancomycin is given, it should be discontinued after 48 hours if cultures remain negative and there is no evidence of methicillin-resistant Staphylococcus aureus (MRSA).

• Patients with a history of antibiotic-resistant organisms may require alternative regimens.

• Antibiotic regimens may be modified as clinical and laboratory data results become available. (However, antipseudomonal coverage should typically continue until absolute neutrophil count [ANC] recovers to >500 cells/mm³.)

• Patients who remain unstable after initial standard neutropenic-fever management should have their regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi.

• After 4-7 days of broad-spectrum antibiotics, empiric antifungal coverage should be added in high-risk patients with persistent fever with no documented source. Treatment regimens include micafungin or liposomal amphotericin B and should be decided in conjunction with an infectious disease (ID) consultation.
  
  

(Source: Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 2011.)

Indications for granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF):

• often administered prophylactically after chemotherapy regimens associated with high incidence of neutropenic fever (see Table 1. Risk of Febrile Neutropenia, According to the Type of Cancer and Chemotherapy Regimen)

• may be given prophylactically after low- or intermediate-risk chemotherapy regimens in older patients or patients with high-risk comorbidities

• may be given to patients who do not receive prophylaxis but do not recover granulocyte counts to facilitate adherence to planned chemotherapy schedule in curative situations

• may be given to patients with neutropenic fever with high risk for infection-associated complications or factors predictive of poor outcome
  
  

Prophylaxis for neutropenic fever: Antibiotic prophylaxis is recommended for patients who are at high risk for bacteremia and/or fungaemia, including patients who are expected to have profound, protracted neutropenia (defined as <100 neutrophils/µL for >7 days) or other risk factors. Although institutional practices may vary, some general guidelines for antimicrobial prophylaxis are as follows:

• Antibacterial prophylaxis with levofloxacin or ciprofloxacin to prevent Pneumocystis jirovecii infection is recommended in high-risk patients, including those undergoing allogenic hematopoietic cell transplantation (HCT) and those receiving induction chemotherapy for acute leukemia.

• Antifungal prophylaxis with oral triazole or parenteral echnocandin is recommended for patients with acute myeloid leukemia, myelodysplastic syndrome, and/or patients treated with HCT.

• Antiviral prophylaxis with acyclovir or valacyclovir is recommended for patients seropositive for herpes simplex virus who are undergoing allogeneic HCT, patients undergoing induction chemotherapy for acute leukemia, and patients seropositive for varicella zoster virus.