Overview
Definition:
Febrile neutropenia (FN) is defined as a single oral temperature of ≥38.0°C (100.4°F) or two readings of ≥37.5°C (99.5°F) sustained over 1 hour, in a patient with neutropenia (absolute neutrophil count [ANC] < 1.5 x 10^9/L, expected to fall below 1.0 x 10^9/L within 48 hours).
Epidemiology:
It is a common and potentially life-threatening complication of cancer chemotherapy and hematopoietic stem cell transplantation (HSCT)
Incidence varies widely depending on the underlying malignancy, treatment regimen intensity, and patient factors, ranging from 20-70% in pediatric oncology patients receiving myelosuppressive therapy.
Clinical Significance:
FN represents a medical emergency due to the profound vulnerability to bacterial, fungal, and viral infections
Prompt recognition and management are crucial to prevent severe morbidity, mortality, and treatment delays, thereby improving outcomes in pediatric cancer patients.
Clinical Presentation
Symptoms:
Fever is the hallmark symptom
Patients may also present with signs of infection such as cough, sore throat, dysuria, diarrhea, abdominal pain, skin lesions, or mucositis
However, classic signs of inflammation (redness, swelling, pus) may be absent or subtle due to the lack of neutrophils.
Signs:
The most critical sign is fever
Other findings might include tachycardia, tachypnea, hypotension, and signs of local infection such as pharyngitis, otitis, skin abscesses, or perianal erythema/tenderness
Mucositis, especially oral mucositis, is a common finding.
Diagnostic Criteria:
The definition of febrile neutropenia itself serves as the primary diagnostic criterion: ANC < 1.5 x 10^9/L (and predicted to decrease) plus fever (single T ≥38.0°C or two T ≥37.5°C sustained over 1 hour).
Diagnostic Approach
History Taking:
Detailed history of recent chemotherapy or HSCT, duration of neutropenia, any recent symptoms suggestive of infection, exposure to sick individuals, travel history, and use of prophylactic medications
Specific questioning regarding pain at any site (e.g., perianal, oral).
Physical Examination:
A thorough physical examination focusing on all body systems, including oral cavity, oropharynx, skin, lungs, abdomen, and perianal region
Careful examination for any focal source of infection
Vital signs assessment is critical.
Investigations:
Complete blood count (CBC) with differential to confirm neutropenia
Blood cultures (peripheral and from central lines if present) are mandatory
Urinalysis and urine culture
Chest X-ray if respiratory symptoms are present
Lumbar puncture if meningitis is suspected
Other cultures (sputum, stool, wound) as indicated by clinical signs
Inflammatory markers like C-reactive protein (CRP) and procalcitonin can aid in assessing infection severity but are not diagnostic alone.
Differential Diagnosis:
Other causes of fever in immunocompromised children, including viral infections (e.g., herpes simplex, influenza), fungal infections (e.g., Candida, Aspergillus), non-infectious inflammatory conditions, and drug fever.
Management
Risk Stratification:
Patients are risk-stratified into low-risk and high-risk groups using validated tools like the Talcott score or MASCC score (modified for pediatrics)
Factors include duration of neutropenia, severity of neutropenia, presence of comorbidities, performance status, and mucositis grade
Low-risk patients may be candidates for oral antibiotics and outpatient management, while high-risk patients require intravenous (IV) antibiotics and inpatient care.
Empiric Antibiotics:
For high-risk FN, broad-spectrum IV antibiotics are initiated empirically immediately after obtaining cultures
Preferred initial regimens include monotherapy with a beta-lactam agent such as piperacillin-tazobactam, cefepime, or meropenem
Vancomycin may be added if there is concern for Gram-positive organisms (e.g., MRSA, catheter-related infection, skin/soft tissue infection, pneumonia, or hemodynamic instability).
Duration Of Therapy:
Antibiotics are continued until the ANC recovers to >0.5 x 10^9/L and is trending upwards, and the patient is afebrile for at least 48 hours
If a specific pathogen is identified, therapy is tailored to the susceptibility pattern
Duration for documented infections may be longer.
Supportive Care:
Fluid resuscitation for hemodynamic instability
Antipyretics for comfort
Prompt management of mucositis
Granulocyte colony-stimulating factors (G-CSFs) are often used to shorten the duration of neutropenia, especially in high-risk patients or those with persistent neutropenia or fever
Antifungal and antiviral prophylaxis/treatment are essential in specific high-risk scenarios.
Complications
Early Complications:
Disseminated bacterial or fungal infections, sepsis, septic shock, multi-organ dysfunction syndrome, pneumonia, necrotizing enterocolitis, and severe mucositis.
Late Complications:
Treatment delays, prolonged hospitalization, increased treatment-related morbidity, and increased risk of mortality
Recurrent episodes of neutropenia may occur.
Prevention Strategies:
Prophylactic antibiotics (e.g., fluoroquinolones, trimethoprim-sulfamethoxazole), antifungal prophylaxis (e.g., fluconazole), and antiviral prophylaxis (e.g., acyclovir) are often used in high-risk patients
G-CSF prophylaxis can also reduce the incidence and duration of neutropenia.
Prognosis
Factors Affecting Prognosis:
The prognosis is strongly influenced by the promptness of treatment, the underlying disease and its treatment intensity, the development of complications, and the patient's overall condition
Early recognition and aggressive empiric antibiotic therapy significantly improve outcomes.
Outcomes:
With timely and appropriate management, the mortality rate associated with febrile neutropenia has significantly decreased
However, it remains a serious complication
Successful management leads to recovery and allows for continuation of potentially curative cancer therapy.
Follow Up:
Close monitoring during and after neutropenic episodes is essential
Follow-up includes assessing for recovery of neutrophil counts, resolution of infection, and managing any long-term sequelae
Patients with recurrent neutropenia may require specialized management and investigation.
Key Points
Exam Focus:
Febrile neutropenia is an oncologic emergency
Immediate broad-spectrum IV antibiotics after blood cultures are paramount
Risk stratification is key to guiding management (outpatient vs
inpatient, oral vs
IV antibiotics)
Recognize that classic signs of infection may be absent
G-CSF use is common in high-risk cases.
Clinical Pearls:
Always suspect FN in any febrile child receiving myelosuppressive therapy
Do not delay antibiotics while awaiting culture results
Consider sources of infection in unusual sites (e.g., perianal)
Review chemotherapy protocols for anticipated nadir periods
Re-evaluate antibiotic choice if fever persists or worsens.
Common Mistakes:
Delaying antibiotic initiation
Failing to obtain blood cultures before starting antibiotics
Inadequate broad-spectrum coverage
Misclassifying patients as low-risk when they are high-risk
Over-reliance on CRP/procalcitonin for diagnosis
Not considering non-bacterial causes of fever.