Febrile Neutropenia: Definition, Diagnostic Criteria, and Causes
Febrile neutropenia is defined as a single oral temperature ≥38.3°C (or ≥38.0°C sustained over 1 hour) combined with an absolute neutrophil count <500 cells/mcL (or <1000 cells/mcL with predicted decline to ≤500 cells/mcL within 48 hours). 1, 2
Diagnostic Criteria
The diagnostic criteria require meeting both fever and neutropenia thresholds simultaneously:
Fever Component
- Single oral temperature ≥38.3°C (101°F), OR 1, 2
- Temperature ≥38.0°C (100.4°F) sustained for at least 1 hour 1, 2
Neutropenia Component
- Absolute neutrophil count (ANC) <500 cells/mcL at presentation, OR 1, 2
- ANC <1000 cells/mcL with predicted decline to ≤500 cells/mcL within the next 48 hours based on chemotherapy timing and trajectory 1, 2
Critical clinical point: Do not wait for the ANC to actually fall below 500 cells/mcL before treating—if chemotherapy timing suggests imminent decline to this threshold, treat immediately as febrile neutropenia. 3
Clinical Significance and Risk Stratification
Febrile neutropenia represents a medical emergency requiring empiric antibiotic therapy within 2 hours of presentation. 3, 2, 4
Mortality Rates
- Overall mortality: 5% in solid tumors (1% in low-risk patients) 3
- Up to 11% in hematological malignancies 3, 2
- 18% with Gram-negative bacteremia 3, 2
- 5% with Gram-positive bacteremia 3
Risk Stratification Using MASCC Score
Patients can be stratified into high-risk and low-risk categories using the Multinational Association for Supportive Care in Cancer (MASCC) scoring system: 1
Duration of neutropenia >7 days significantly increases infection risk and mortality, making this a critical prognostic factor. 3, 2
Common Causes
Primary Etiology
Myelosuppressive chemotherapy is the predominant cause of febrile neutropenia in cancer patients. 1, 5 The condition typically occurs within 6-8 days after standard chemotherapy administration. 5
High-Risk Chemotherapy Regimens (>20% FN Risk)
The NCCN guidelines classify specific chemotherapy regimens by their risk of causing febrile neutropenia: 1
Hematologic Malignancies:
- ALL induction regimens 1
- BEACOPP for Hodgkin lymphoma 1
- ICE, RICE, CHOP-14, DHAP, ESHAP, HyperCVAD + rituximab for non-Hodgkin's lymphomas 1
Solid Tumors:
- TAC (docetaxel, doxorubicin, cyclophosphamide) for breast cancer 1
- Dose-dense AC followed by paclitaxel for breast cancer 1
- MVAC for bladder cancer 1
- Dacarbazine-based combinations for melanoma 1
Infectious Organisms
When infection is documented (approximately 28-29% of cases have positive cultures): 5, 6
Bacterial Pathogens:
- Gram-positive bacteria (currently predominant) 5
- Gram-negative bacteria (historically dominant in 1970s, still associated with highest mortality) 1, 5
- At least 20% of patients with ANC <100 cells/mcL develop bacteremia 2
Other Pathogens:
- Fungal infections (particularly in persistent fever after 4-6 days of antibiotics) 4
- Viral infections 5
Clinical Presentation Nuances
Fever is often the only sign of infection in neutropenic patients, as other inflammatory signs and symptoms are diminished or absent due to lack of neutrophils. 1, 3, 2 Even minor skin lesions warrant thorough evaluation as they can represent serious disseminated infections. 1, 3
Approximately 43-48.9% of febrile neutropenia episodes are classified as unexplained fevers with no identifiable focus of infection despite thorough evaluation. 7, 6
Common Pitfalls to Avoid
- Delaying treatment while waiting for ANC to drop below 500 cells/mcL—treat based on predicted decline 3
- Underestimating minor skin lesions—these can represent life-threatening disseminated infections in neutropenic patients 1, 3
- Failing to obtain blood cultures before antibiotic administration—at least 2 sets should be drawn from peripheral sites and all central line lumens 1, 4
- Delaying empiric antibiotics—earlier administration is associated with fewer complications and reduced mortality 3