Hematology / Oncology

Neutropenic Fever in Pediatric Cancer Patients

Introduction

What is it?

Neutropenia in the pediatric cancer patient: absolute neutrophil count (ANC) < 500 cells/microliter or ANC that is expected to decrease to <500 cells/µL in next 48 hours.
Fever: generally defined as a single oral temperature >to 38.3°C (101° F) in neutropenic patient; a temperature > 38° C (100.4° F) for one hour or two elevations; a temperature >38° C (100.4° F) during a 12-hour period are additional definitions that may be used
- Rectal temperature is never to be used due to the risk of mucosal damage and associated bacteremia

Why does it matter?

Infectious complications from chemotherapy-induced myelosuppression are a major cause of morbidity and mortality in pediatric cancer patients.
Neutropenic fever is one of the most common reasons for ED visits among pediatric cancer patients.

Etiology of Fever

Febrile neutropenia may be diagnosed as fever of unknown origin in approximately 70% of patients

However, infection is documented in 10-40% of neutropenic fever patients
- Infectious etiologies:
  - Bacteremia most common
  - Other sources include GI tract, urinary tract, respiratory tract, skin
- Gram positives often now identified as source of bacteremia, which is thought to be partially due to the increasingly frequent use of prophylactic antibiotics in pediatric patients receiving chemotherapy
- Common gram positives isolated from the blood: coagulase negative staphylococcus species (spp), viridans streptococcal spp, Staphylococcus aureus (including MRSA)
- Common aerobic gram negatives: E. coli, Klebsiella spp, Pseudomonas spp, Acinetobacter spp, Enterobacter spp
- Fungi less commonly can be recovered: Candida spp most common
- Most common viral etiologies: herpes simplex and varicella-zoster

Evaluation

Start with a thorough, but targeted history:
- It is important to ask about site-specific symptoms, antimicrobial prophylaxis, infection exposures, chemotherapy agents used and stage of therapy (to anticipate the length of the neutropenic episode), intravascular catheters
Physical exam should focus on:
- Abnormal vital signs (particularly tachycardia, even without hypotension)
- Skin, sinuses, oropharynx (attention to gingiva), lungs, abdomen, perineum (particularly perianal and labial regions)
- Remember that signs of inflammation in a neutropenic patient may be subtle! Mild erythema or tenderness should not be ignored
Labs/Imaging:
- Obtain blood cultures without delay
  - Obtaining more than one culture is helpful – if coagulase-negative staphylococcal spp are isolated from two or more blood cultures, true bacteremia is more likely than contamination of the specimen
  - Cultures should be taken from each lumen of a central line when possible
  - Consider obtaining cultures from both central and peripheral lines:
    - Studies show that obtaining cultures in this manner can help differentiate a catheter-related infection from bacteremia from another source
- Always order a CBC w/ differential, BMP, liver transaminases and total bilirubin
- Cultures/images of other sites of suspected infection (i.e. CXR, LP, biopsy from skin)
- CRP and lactate can also be considered but are not essential
- Consider urinalysis/urine culture in young patients who may not complain of UTI symptoms

Treatment

Broad-spectrum antibiotics should be started as soon as cultures are obtained (within 60 minutes of presentation)
- More than 60 minute delay has been associated with increased risk of adverse effects and longer length of stay
The details of management depends on whether a patient is classified as low-risk or high-risk
- High-risk patients: neutropenia (ANC <500 cells/µL) anticipated to last >7 days; hepatic or renal insufficiency; or comorbid medical problems.
- Low-risk patients: neutropenia expected to resolve within 7 days; stable and adequate hepatic and renal function; and no active comorbidities

Febrile Neutropenia_Algorhythm_0.png

Initial management of fever and neutropenia. *Limited data to support recommendation. ANC, absolute neutrophil count; CT, computed tomography; MRI, magnetic resonance imaging. Adapted from Alison G. Freifeld et al. Clin Infect Dis. 2011;52:e56-e93. Click here for larger image.

Initial therapy with a broad-spectrum antipseudomonal beta-lactam (e.g., cefepime or ceftazidime), a carbapenem (e.g., meropenem or imipenem-cilastatin), or piperacillin-tazobactam is recommended for uncomplicated episodes of fever in neutropenic patients
- Studies have demonstrated that empiric monotherapy with these agents is as efficacious as combination therapy but with fewer adverse events
- If a carbapenem is to be used, meropenem is preferred due to risk of seizures with imipenem-cilastatin
Additional therapies may be needed based on clinical presentation
- For example, consider addition of metronidazole for abdominal symptoms, particularly pain or blood per rectum
The 2010 Infectious Diseases Society of American (IDSA) guidelines recommend that vancomycin be reserved for the following clinical scenarios:
- Hypotension or other signs of cardiopulmonary deterioration
- Radiographically documented pneumonia
- Clinically suspected central venous line site infection (eg, chills or rigors with infusion through the catheter and cellulitis around the catheter entry or exit site)
- Skin or soft tissue infection at any site
- Known colonization with MRSA, penicillin- and cephalosporin-resistant Streptococcus pneumoniae
- When a blood culture has been reported to be growing gram-positive bacteria and identification and susceptibility testing are pending
Empiric antifungal therapy may be added for high-risk patients who have persistent fever after 4-7 days of broad-spectrum antibiotics and no identified source; lipid formulations of amphotericin B often used; may also consider CT of sinuses and chest, serial fungal serology
Endpoint for therapy: negative cultures after 48 hours, afebrile for at least 24 hours, and evidence of marrow recovery
- Pediatric studies did not define threshold for marrow recovery but 2010 IDSA guidelines suggests an increasing ANC that exceeds 500 cells/microliter
For further guidance, the following algorithm has been developed as a guideline for management of neutropenic fever patients after 2-4 days of empiric antibiotics

Reassess after 2-4 days of empirical antibiotic therapy. ANC, absolute neutrophil count; CT, computed tomography; IV, intravenous; MRI, magnetic resonance imaging. Adapted from Alison G. Freifeld et al. Clin Infect Dis. 2011;52:e56-e93. Click here for larger image.

Granulocyte-colony stimulating factor (G-CSF)/ Granulocyte-macrophage colony-stimulating factor GM-CSF

Most pediatric studies agree that prophylactic use decreases the duration of neutropenia
Conflicting data regarding their impact on rates of febrile neutropenia, days of intravenous (IV) antibiotics use, rates of documented infection, and length of hospital stay
2010 IDSA guidelines recommend prophylactic use in patients who have at least a 20% risk of developing neutropenic fever
No strong data to suggest that there are significant benefits to using colony stimulating factors in the midst of neutropenic fever episode

Possible Future Directions: Granulocyte Transfusion (GTX)

GTX has been studied for decades as treatment option for neutropenia
However, GTX is rarely used in chemotherapy or HCT-induced neutropenia patient population
- No randomized, prospective study has been done yet in pediatric cancer patients with neutropenic fever to assess the utility of GTX in addition to anti-microbial therapy
- Side effects
  - Mild to moderate transfusion reactions in 25-50% of recipients.
    - slow infusion and premedication can reduce incidence and severity
  - Moderate to severe pulmonary adverse reactions: cough, dyspnea, hypoxia, changes on chest radiograph
- Inconvenient for donors: have to get screened, receive steroids and G-CSF (these medications increase the number of granulocytes that can be collected from donor and prolong their survival) before they can donate
- Donors are also at risk for mild side effects: headaches, arthralgia, bone aches, fatigue and insomnia most common
Studies suggest that GTX may help resolve infection in pediatric patients with prolonged neutropenia and severe infection unresponsive to antimicrobials (Diaz et al., 2014; Sachs et al., 2006)

Helpful Links:

For further information on this topic, click the following links:
- 2010 IDSA guidelines: http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/FN.pdf
- 2012 International Pediatric Fever and Neutropenia Guideline Panel guidelines: http://jco.ascopubs.org/content/30/35/4427.full.pdf
- University of Chicago Pediatrics ED guidelines: http://pediatrics.uchicago.edu/chiefs/PER/documents/clinical%20guidelines%20word%20docs/HemeOnc-FeverandNeutropenia%20December%202013.pdf

References:

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