Febrile Neutropenia

Definitions and Severity Grading

Neutropenia is defined as a decrease in the absolute number of circulating segmented neutrophils and band forms in the peripheral blood. The absolute neutrophil count is calculated by multiplying the total white blood cell count by the percentage of segmented neutrophils plus bands. Normal neutrophil counts must always be stratified for the age and race of the patient.

Etiology of Neutropenia

Neutropenia can be classified as acquired or inherited. In the context of febrile neutropenia, acquired causes such as chemotherapy or severe systemic infections are the most common triggers.

Pathophysiology and Clinical Manifestations

Patients with an absolute neutrophil count below 500 /$\mu$L are at a substantial risk for developing infections.

• These infections primarily arise from the patient's endogenous flora as well as from nosocomial organisms.
• The integrity of the skin and mucous membranes significantly influences the risk of infection.
  • Mucositis and the presence of indwelling central venous lines predispose patients to a much greater risk of infection.
• The usual signs and symptoms of local infection and inflammation may be markedly diminished.
  • This includes a lack of exudate, fluctuance, and regional lymphadenopathy.
  • The diminished response is directly due to the inability to form pus in the absence of neutrophils.
• Despite the lack of localizing signs, patients with agranulocytosis still experience fever and feel pain at sites of inflammation.

Common Sites and Pathogens

• The most common clinical presentation includes fever, frequent infections, aphthous stomatitis, and gingivitis.
• Localized infections frequently include cellulitis, furunculosis, perirectal inflammation, colitis, sinusitis, and otitis media.
• Serious and life-threatening infections include pneumonia, deep tissue abscess, and sepsis.
• The most common bacterial pathogens causing infections in neutropenic patients are Staphylococcus aureus and gram-negative bacteria.
  • Central venous catheter-related infections are frequently caused by Staphylococcal species and Candida species.
  • Multidrug-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae are also highly significant pathogens.
• Viral infections can also cause severe lower respiratory tract disease during periods of profound neutropenia.
  • Seasonal respiratory viruses include influenza, respiratory syncytial virus, parainfluenza virus, and human metapneumovirus.

Evaluation and Risk Stratification

The initial approach to a pediatric patient with fever and neutropenia requires rapid assessment and the implementation of a validated risk stratification strategy.

Risk Stratification

Risk stratification should be adopted and incorporated into routine clinical management.

• High-risk patients include those undergoing allogeneic hematopoietic stem cell transplantation.
  • Patients with prolonged neutropenia are also considered high risk.
  • Children receiving high-dose corticosteroids are at high risk for invasive fungal disease.
• Low-risk patients are those without prolonged neutropenia or severe immunosuppressive features.
  • These patients may be candidates for outpatient management if adequate infrastructure exists.

Initial Laboratory and Imaging Evaluation

• Blood cultures must be obtained immediately at the onset of fever and neutropenia.
  • Cultures must be drawn from all lumens of central venous catheters.
  • Clinicians should consider obtaining peripheral blood cultures concurrently with central venous catheter cultures.
• A urinalysis and urine culture should be considered if a clean-catch midstream specimen is readily available.
• Chest radiography should only be obtained in patients presenting with specific respiratory signs or symptoms.

Management of Fever and Neutropenia

Management approaches include the use of prophylactic antimicrobials, preemptive antimicrobials, and therapeutic empirical antibiotics.

Initial Empirical Antibacterial Therapy

Ongoing Management and Therapy Modification

• Careful daily reassessment of the patient's clinical status is required.
• In patients who are responding to the initial empirical antibiotic therapy, modifications should be made swiftly.
  • Discontinue double coverage for gram-negative infections or empirical glycopeptides after 24 to 72 hours.
  • This should be done if there is no specific microbiologic indication to continue combination therapy.
• Do not modify the initial empirical antibacterial regimen solely based on persistent fever in children who remain clinically stable.
• In children with persistent fever who become clinically unstable, the initial empirical regimen must be escalated.
  • Escalation should include broader coverage for resistant gram-negative, gram-positive, and anaerobic bacteria.

Empirical Antifungal Management

Prolonged neutropenia carries a high risk of invasive fungal disease. Invasive fungal disease represents a life-threatening complication that significantly affects patient outcomes.

Fungal Diagnostics

• In high-risk patients with prolonged fever and neutropenia ($\ge$ 96 hours), serum galactomannan should generally not be used to guide empirical antifungal management.
• Do not use $\beta$-D-glucan testing in this setting.
• Do not use fungal polymerase chain reaction testing in the blood.
• Perform a computed tomography scan of the lungs to evaluate for fungal pulmonary disease.
• Consider imaging of the abdomen in patients even without localizing signs or symptoms.
• Do not routinely perform computed tomography of the sinuses in patients without localizing signs or symptoms.

Fungal Treatment

• Initiate caspofungin or liposomal amphotericin B for empirical antifungal therapy.
  • This is indicated in high-risk patients with prolonged fever and neutropenia ($\ge$ 96 hours) that is unresponsive to broad-spectrum antibacterial agents.
• In low-risk patients with prolonged fever and neutropenia ($\ge$ 96 hours), clinicians should consider withholding empirical antifungal therapy.

Cessation of Antimicrobial Treatment

• Empirical antibiotics should be discontinued in all patients who meet specific recovery criteria.
  • Blood cultures must be negative at 48 hours.
  • The patient must have been afebrile for at least 24 hours.
  • There must be evidence of bone marrow recovery and rising neutrophil counts.

Adjunctive Therapies

Granulocyte Colony-Stimulating Factor

• Granulocyte colony-stimulating factor therapy is generally effective at raising the absolute neutrophil count.
• The routine use of granulocyte colony-stimulating factor is not universally indicated for all acute episodes of febrile neutropenia but is highly valuable in specific hypoproliferative states.
  • It is used for patients with severe chronic neutropenia and symptomatic idiopathic neutropenias.
  • For drug-induced neutropenia, subcutaneous administration of recombinant human granulocyte colony-stimulating factor should be considered if the patient is symptomatic with infection.

Granulocyte Transfusions

• Granulocyte transfusions have historically been used sparingly in older infants and children.
• They may be considered for patients with neutropenic infections when severe neutropenia is prolonged.
  • The primary indication is severe neutropenia with a bacterial, yeast, or fungal infection that is unresponsive or progressive despite appropriate antimicrobial therapy.
• The preferred granulocyte dose requires donors to be stimulated with granulocyte colony-stimulating factor plus dexamethasone.
• Transfusions should be given daily until either the infection resolves or the blood neutrophil count is sustained above 1500 /$\mu$L for a few days.