Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients

Publication Date: January 22, 2023
Last Updated: January 31, 2023

SECTION A: INITIAL PRESENTATION OF FN

Initial Management: Risk Stratification
  • A1. Adopt a validated risk stratification strategy and incorporate it into routine clinical management (strong recommendation, low-quality evidence).

Initial Management: Evaluation
  • A2. Obtain blood cultures at the onset of FN from all lumens of central venous catheters (strong recommendation, low-quality evidence).
  • A3. Consider obtaining peripheral blood cultures concurrent with central venous catheter cultures (conditional recommendation, moderate-quality evidence).
  • A4. Consider urinalysis and urine culture in patients where a clean-catch, mid-stream specimen is readily available (conditional recommendation, low-quality evidence).
  • A5. Obtain chest radiography only in patients with respiratory signs or symptoms (strong recommendation, moderate-quality evidence).

Initial Management: Treatment
  • A6. In high-risk FN
    • A6a. Use monotherapy with an antipseudomonal β-lactam, a fourth-generation cephalosporin or a carbapenem as empiric antibacterial therapy in pediatric high-risk FN (strong recommendation, high-quality evidence).
    • A6b. Reserve addition of a second anti-Gram-negative agent or a glycopeptide for patients who are clinically unstable, when a resistant infection is suspected, or for centers with a high rate of resistant pathogens (strong recommendation, moderate-quality evidence).
  • A7. In low-risk FN
    • A7a. Consider initial or step-down outpatient management if the infrastructure is in place to ensure careful monitoring and follow-up (conditional recommendation, moderate-quality evidence).
    • A7b. Consider oral antibacterial therapy administration if the patient is able to tolerate this route of administration reliably (conditional recommendation, moderate-quality evidence).

SECTION B: ONGOING MANAGEMENT OF FN EXCLUDING EMPIRIC ANTIFUNGAL THERAPY

Ongoing Management: Modification of Treatment
  • B1. In patients who are responding to initial empiric antibacterial therapy, discontinue double coverage for Gram-negative infection or empiric glycopeptide (if initiated) after 24-72 hours if there is no specific microbiologic indication to continue combination therapy (strong recommendation, moderate-quality evidence).
  • B2. Do not broaden the initial empiric antibacterial regimen based solely on persistent fever in patients who are clinically stable (strong recommendation, low-quality evidence).
  • B3. In patients with persistent fever who become clinically unstable, escalate the initial empiric antibacterial regimen to include coverage for resistant Gram-negative, Gram-positive and anaerobic bacteria (strong recommendation, very-low-quality evidence).
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​​​​​​​Ongoing Management: Cessation of Treatment
  • B4. In both high-risk and low-risk FN patients who have been clinically well and afebrile for at least 24 hours, discontinue empiric antibacterial therapy if blood cultures remain negative at 48 hours if there is evidence of marrow recovery (strong recommendation, low-quality evidence).
  • B5. In patients with low-risk FN who have been clinically well and afebrile for at least 24 hours, consider discontinuation of empiric antibacterial therapy if blood cultures remain negative at 48 hours despite no evidence of marrow recovery (conditional recommendation, moderate-quality evidence)

SECTION C: EMPIRIC ANTIFUNGAL THERAPY

Empiric Antifungal Therapy: Risk Stratification
  • C1. Invasive fungal disease (IFD) high-risk patients are those with acute myeloid leukemia, high-risk acute lymphoblastic leukemia or relapsed acute leukemia; those with prolonged neutropenia; those receiving high-dose steroids; and those undergoing allogeneic HCT in the first year after HCT without evidence of T-cell reconstitution, or receiving steroids or multiple immune suppressive agents to prevent or treat graft-versus-host disease. Those not meeting these criteria are categorized as IFD low-risk patients (strong recommendation, low-quality evidence).

Empiric Antifungal Therapy: Evaluation
  • C2. In terms of biomarkers to guide empiric antifungal management for prolonged (≥ 96 hours) FN in IFD high-risk patients:
    • C2a. Consider not using serum galactomannan (conditional recommendation, moderate-quality evidence).
    • C2b. Do not use β-D-glucan (strong recommendation, low-quality evidence).
    • C2c. Do not use fungal polymerase chain reaction testing in blood (strong recommendation, moderate-quality evidence).
  • C3. In terms of imaging for the evaluation of prolonged (≥ 96 hours) FN in IFD high-risk patients:
    • C3a. Perform computed tomography (CT) of lungs (strong recommendation, low-quality evidence).
    • C3b. Consider imaging of abdomen such as ultrasound (conditional recommendation, low-quality evidence).
    • C3c. Consider not routinely performing CT of sinuses in patients without localizing signs or symptoms (conditional recommendation, low-quality evidence).

Empiric Antifungal Therapy: Treatment
  • C4. In IFD high-risk patients with prolonged (≥ 96 hours) FN unresponsive to broad-spectrum antibacterial therapy, initiate caspofungin or liposomal amphotericin B for empiric antifungal therapy unless a pre-emptive antifungal therapy approach is chosen (strong recommendation, high-quality evidence).
  • C5. In non-HCT IFD high-risk patients not receiving anti-mold prophylaxis with prolonged (≥ 96 hours) FN unresponsive to broad-spectrum antibacterial therapy, consider a pre-emptive antifungal therapy approach by deferring empiric antifungal therapy and initiating antifungal therapy only if evaluation suggests or indicates IFD (conditional recommendation, moderate-quality evidence).
  • C6. In IFD low-risk patients with prolonged (≥ 96 hours) FN, consider withholding empiric antifungal therapy (conditional recommendation, low-quality evidence).
  • Good practice statement 1. For febrile patients who are clinically unstable, initiate FN CPG-consistent empiric antibacterial therapy as soon as possible.

Recommendation Grading

Overview

Title

Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients

Authoring Organization

Consensus and Physician Experts

Publication Month/Year

January 22, 2023

Last Updated Month/Year

April 1, 2024

Document Type

Guideline

Country of Publication

US

Document Objectives

To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell transplantation recipients.

Target Patient Population

Pediatric patients age 0-18 years receiving chemotherapy for cancer and recipients of HCT

Target Provider Population

All health care professionals who are concerned with infectious complications in pediatric patients receiving cancer treatments

Inclusion Criteria

Male, Female, Adolescent, Child, Infant

Health Care Settings

Ambulatory, Hospital, Laboratory services, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Assessment and screening, Treatment, Management

Diseases/Conditions (MeSH)

D064147 - Febrile Neutropenia, D009503 - Neutropenia, D018380 - Hematopoietic Stem Cell Transplantation, D006412 - Hematopoietic Stem Cells

Keywords

fever, neutropenia, neutropenic fever, Fever and Neutropenia, Hematopoietic cell transplantation, HCT

Supplemental Methodology Resources

Data Supplement