We all are well aware of the prevalence “fever” as a presenting complaint. We are also well aware that not all “cc: fever” are created equal. Fever in a neonate may be due to a virus, but we can’t bet on it. Fever in the patient with delayed cap refill requires more contemplation than what is the maximum dose of antipyretic. Fever in a patient with sickle cell disease warrants special attention. While, generally, I have a disdain for making medical decisions based heavily on the WBC count (“WBC count is the Last Bastion of the Intellectually Destitute” – Dr. Amal Mattu @amalmattu), there are conditions that mandate respect for the WBC, like leukemia and childhood cancers. Let us take a minute to review the current recommendations for initial management of Neutropenic Fever:

Neutropenic Fever: Basics

• Neutropenia definitions can vary between institutions. [White, 2014]
  • Typical definition = Absolute Neutrophil Count (ANC) < 1500 cell/microL
  • Severe neutropenia is ANC < 500
• Patients receiving chemotherapy are at high risk for morbidity and mortality due to infections! [Cohen, 2016]
  • The reduced immune system may lead these patients to present with limited or atypical signs of illness.
  • Fever may be the only sign of significant infection.
• Neutropenic fever is one of the most common and serious complicationsthat occurs during chemotherapy. [Lehrnbecher, 2017;Klastersky, 2016]

Low vs High Risk?

• There are a number of scoring systems used to assess a patient’s risk of bacteremia and morbidity/mortality. [Lehrnbecher, 2017]
• None of them are universally agreed upon. [Lehrnbecher, 2017; Cohen, 2016]
  • There are 6 clinically based low-risk stratification strategies.
  • All still require local validation. [Lehrnbecher, 2017]
• Factors known to increase risk:
  • Chemotherapeutic regimen
  • Advanced disease or progressive disease
  • AML, ALL, Burkitt lymphoma, and relapsed acute leukemia
  • History of hematopoietic stem-cell transplantation
  • History of prior febrile neutropenia
  • Use of high dose corticosteroids
  • Presence of a focal site of infection (ex, pneumonia, abscess)
  • Presence of central venous access
  • Mucositis
  • Absolute Monocyte Count <100/microL

Neutropenic Fever: ED Evaluation

• While signs and symptoms may be minimal, there presence is important!
• Search for:
  • Complaints of chills or rigors
  • Hypotension
  • Poor Perfusion
  • A Source!
    • Mucositis
    • Abscess
    • Pulmonary
    • Urinary tract
    • GI tract
    • Perineal region infection
    • Necrotizing Fasciitis (localized pain out of proportion) [Johnston, 2001]
    • CNS infection
  • Don’t skimp on the labs!
    • CBC with differential (obviously, need this to confirm neutropenia)
    • Blood cultures
      • From all lumens of central line
      • May also obtain peripheral culture as this can increase the detection of true bacteremia by 12%, but must be weighed against risk of contamination and pain. [Lehrnbecher, 2017]
    • Cultures of other potential sources
    • Urinalysis and Urine Culture, even if asymptomatic [Lehrnbecher, 2017; Sandoval, 2012]
    • Basic electrolyte panel
    • Chest Xray only for patients with pulmonary signs/symptoms. [Lehrnbecher, 2017; Roberts, 2012]

Neutropenic Fever: Initial Management

• DON’T JUST WAIT, RESUSCITATE!
  • Again, being aware that chemotherapy may lead to subtle presentations, the patient/family may not become alert to illness until the child is much sicker.
  • IV or IO boluses fluids if perfusion is poor or hypotension present.
  • Empiric broad spectrum dual therapy antibiotics
    • Antipseudomonal Beta-Lactam, 4th generation cephalosporin, or carbapenem PLUS a second gram-negative agent or a glycopeptide for the clinically unstable is recommended. [Lehrnbecher, 2017]
    • Dual coverage is also recommended if a resistant infection is suspected. [Lehrnbecher, 2017]
    • Ex: Cefepime AND Aminoglycoside AND Vancomycin
    • Tailor to the patient’s prior culture results and hospital resistance patterns
  • Early use of pressors if need be.
• IF THE CHILD LOOKS WELL, DON’T BE CAVALIER!
  • Again, presentation can be subtle in these patients with non-functioning immune systems.
  • Having a institutional protocol for evaluation and management of pediatric neutropenic fever can help expedite care and decrease time to antibiotic administration. [Cohen, 2016; Cash, 2014]
  • Obtain labs, including cultures and give empiric antibiotics.
    • If the child looks well, then empiric mono-therapy is recommended. [Lehrnbecher, 2017; Chuang, 2002]
    • If there is a documented neutropenia in the last 24 hours, treat empirically with monotherapy antibiotics (ex, Cefepime).
    • Due to the high incidence of infections with patients presenting with neutropenic fever, some advocate for giving empiric antibiotics even prior to confirmation of neutropenia in patients with: [Cohen, 2016]
      • Active Chemotherapy regimens (or off less than 1 month) OR
      • History of congenital or acquired neutropenia not related to chemo.
    • Some children will be able to go home on oral antibiotics, but this will be contingent upon assessment of being “low risk” with the Oncologist. [Lehrnbecher, 2017]

Moral of the Morsel

• Don’t be fooled. The patient with no immune system deserves significant respect and requires our vigilance.
• Be thorough.Where is the source? Look at the mucous membranes and consider necrotizing fasciitis (i.e., look in the perineum)!
• Be aggressive! If the child looks sick, throw all of the antibiotics at them. If the child looks well, mono-therapy is recommended.
• High Risk vs Low Risk… don’t decide alone. Your physical exam and lab results will help determine whether a patient is high risk or low risk, but that determination should be made concurrently with the patient’s oncologist.

References