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Neutropenic fever aka febrile neutropenic, it’s not just a clever name!
Kashlak Pearl: It’s important to account for the expected trajectory of the ANC over the next several days (expert opinion).
Dr. Seo considers the expected duration and severity of neutropenia in determining risk. Most patients with solid tumors generally have mild and short duration neutropenia (usually under 7 days). She also factors in comorbidities (especially kidney, liver, or lung disease), distance a patient lives from the hospital, their social support, and ability to follow up.
Note: Guidelines recommend giving the first dose of antibiotic in the clinic, hospital, or ED and observing patients for at least 4 hours before discharge to home (Taplitz, 2018).
Risk scores: Patients with a MASCC score above 21 (or a CISNE score under 3) are also considered low risk .
Note: Do not apply these scores to patients with hemodynamic instability. Also, clinical gestalt is important and can trump scores.
Dr. Seo recommends attention to the skin (rashes, indwelling lines, bone marrow biopsy sites), GI tract (e.g. mucositis, intestines, perirectal area), and the lungs.
Kashlak pearl: A visual inspection of the rectum/perirectal area is appropriate, but it’s probably a good idea to avoid a digital rectal exam (expert opinion).
Send at least 2 sets of blood cultures from different sites (Taplitz, 2018). Draw cultures from each lumen of any central lines, and peripheral blood cultures (expert opinion) with first neutropenic fever.
Send a CBC, CMP, and *lactate [ ASCO/IDSA guideline – Taplitz, 2018 ]. Dr. Seo does not generally send lactate for all patients (expert opinion).
Conditional studies: Guidelines do not recommend chest xray, urine, stool and respiratory viral testing for all patients (Freifeld, 2011). These tests should be based on the clinical presentation. Urine cultures are low yield unless a patient has symptoms referable to the urinary tract, or a urinary tract cancer (expert opinion). Send stool studies in patients with diarrhea. Dr. Seo prefers a chest xray in most patients since neutropenic patients may lack the classic symptoms of pneumonia (expert opinion). Viral swabs for COVID-19, influenza, and other common pathogens may be considered.
Kashlak pearl: Pyuria may be absent in the neutropenic patient.
IV agents: Piperacillin-tazobactam, or cefepime are first line at most institutions. Carbapenems -Imipenem, or meropenem can be considered. [IDSA 2010 Update Abx in Neutropenia – Freifeld, 2011]
*Ceftazidime: Dr. Seo notes that the lack of gram positive spectrum has made this choice less attractive.
Oral agents: Amoxicillin-clavulanate plus fluoroquinolone (FQ); or Clindamyin plus FQ (if penicillin allergic).
Stop antibiotics when:
Dr. Seo recommends stopping all antimicrobial agents at once when the above criteria are met, rather than in a stepwise fashion (expert opinion).
These patients often have prolonged, profound neutropenia (i.e. ANC under 100 for more than 7 days). The prototypical patients are undergoing induction chemotherapy for acute leukemia, or receiving cytotoxic chemotherapy prior to an allogeneic stem cell transplant.
Other factors considered high-risk in the guidelines include “significant medical comorbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes.” (Freifeld, 2011)
Piperacillin-tazobactam, or cefepime are the workhorse agents. Carbapenems are an option for select patients.
When to add vancomycin?: It’s not routinely recommended. Empiric vancomycin is appropriate if history of MRSA infection, in patients with pneumonia, concern for central line-associated infection, skin/soft tissue infection, or hemodynamic instability (Freifeld, 2011).
Fungal infections are more common after prolonged neutropenia (>7 days) and/or prolonged antibiotic use. The IDSA guidelines recommend adding empiric antifungal coverage when fever persists or recurs after 4-7 days of empiric antibiotics, positive serum fungal markers, imaging evidence of fungal infection, or positive fungal cultures (Freifeld, 2011).
Empiric antifungal agents: Amphotericin B (gold standard), echinocandins, or azoles (e.g. voriconazole).
The IDSA guidelines state that patients who complete treatment with resolution of clinical symptoms, but who remain neutropenic can be placed on antibiotic prophylaxis (e.g. fluoroquinolone) until marrow recovery (Freifeld, 2011). However, the How Long Study questioned this practice suggesting that empiric antibiotics can be discontinued after 72 hours without fever, and clinical recovery irrespective of their neutrophil count (Aguilar-Guisado, 2017). Based on our discussion with Dr. Seo, many centers are reviewing the data and thinking on whether it can be implemented.
G-CSF can be given prophylactically with chemotherapy to prevent or shorten the duration of neutropenia.
G-CSF is not recommended during an episode of febrile neutropenia by the IDSA guidelines (Freifeld, 2011), but ASCO guidelines recommend use in patients who are at high risk for infection-associated complications, or who have prognostic factors that are *predictive of poor clinical outcomes (Smith, 2015). Use of G-CSF appears to shorten the duration of neutropenia, and hospital stay, but did not affect overall mortality (Cochrane 2014). Clinical practice varies with some oncologists preferring to give G-CSF and others preferring to forgo it.
*Predictors of poor clinical outcomes based on the ASCO guidelines include expected prolonged (>10 days) and profound neutropenia (ANC <100), age over 65 years, uncontrolled primary disease, pneumonia, hypotension and multiorgan dysfunction (sepsis syndrome), invasive fungal infection, or hospitalization at the time of fever development (Smith, 2015).
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Listeners will develop a framework to approach the prevention, evaluation, and management of febrile neutropenia
After listening to this episode listeners will…
Dr Seo reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
Watto MF, Seo SK, Williams PN. “#288 Neutropenic Fever”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date August 2, 2021.
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