#288 LIVE! Neutropenic Fever featuring Dr. Susan Seo

August 2, 2021 | By Matthew Watto, MD

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Credits

• Writer and Producer: Matthew Watto MD, FACP
• Infographic: Edison Jyang
• Cover Art: Kate Grant MBChb, MRCGP
• Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP   
• Reviewer: Matthew Watto MD, FACP
• Editor: Matthew Watto MD (written materials); Clair Morgan of nodderly.com
• Guest: Susan Seo MD

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Show Segments

• Intro, disclaimer, guest bio
• Guest one-liner, Picks of the Week*
• Case from Kashlak; Definitions
• Initial workup for neutropenic fever 
• Low risk neutropenic fever
• High risk neutropenic fever
• When to add antifungal coverage, G-CSF
• Audience questions
• Outro

Neutropenic Fever Pearls

1. Low risk patients have short, mild neutropenia, lack comorbidities (esp. Lung, kidney or liver disease), live w/in 60 min, have social support, and the ability to follow up.
2. High risk patients have prolonged, severe neutropenia, medical comorbidities, sepsis, or organ dysfunction. These patients should be admitted for IV antibiotics. 
3. Antibiotics can be stopped once febrile symptoms resolve, the ANC is above 500, and after treatment of any identified infections 
4. Send a CBC, CMP, lactate, and blood cultures from at least two sites. Add CXR, urine, stool, and viral studies based on clinical suspicion.
5. Empiric antifungal coverage can be added after prolonged (>4 to 7 days) neutropenic fever with expected neutropenia of >7 days
6. The main role of G-CSF is in preventing neutropenia or shortening the duration. Routine use is NOT recommended during febrile neutropenia

Neutropenic Fever Show Notes

Definitions

Neutropenic fever aka febrile neutropenic, it’s not just a clever name!

• Neutropenia = absolute neutrophil count (ANC) under 1000/microliter
• Severe Neutropenia = ANC under 500
• Profound Neutropenia = ANC under 100
• Fever = A single temp above 101F (38.3C) or a temp >100.4F (38C) sustained for 1 hour 

[ ASCO/IDSA guideline – Taplitz, 2018 ] 

Kashlak Pearl: It’s important to account for the expected trajectory of the ANC over the next several days (expert opinion).

Who can be managed outpatient?

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 . 

1. MASCC score: symptom severity, hypotension, active COPD, cancer type (solid lower risk than hematologic), dehydration, outpatient vs inpatient status, age <60
2. CISNE score: stress induced hyperglycemia, ECOG >=2, COPD, Chronic CVD, NCI mucositis score >=2, monocytes <200

Note: Do not apply these scores to patients with hemodynamic instability. Also, clinical gestalt  is important and can trump scores.

The physical exam

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). 

Labs and imaging

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. 

Antibiotics for neutropenic fever

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). 

Antibiotics duration

Stop antibiotics when: 

1. Patient has defervesced (usually <=72 hours) 
2. ANC is above 500
3. Patient has completed treatment for any identified infection (e.g.  pneumonia, UTI, etc.) —Freifeld, 2011. 

Dr. Seo recommends stopping all antimicrobial agents at once when the above criteria are met, rather than in a stepwise fashion (expert opinion).

High Risk Neutropenia

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)

Initial antibiotics for high risk 

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). 

When to add antifungal coverage

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).

Antibiotics duration in high risk patients

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.

Does G-CSF help treat neutropenic fever?

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).

Links*

1. The Vanishing Half (book)
2. The Sick Extinction (book)
3. Nintendo Switch (handheld system)
4. Animal Crossing (game)
5. I Care A Lot (Netflix film)
6. The Goldfinch (book)

*The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on our Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra.

Goal

Listeners will develop a framework to approach the prevention, evaluation, and management of febrile neutropenia

Learning objectives

After listening to this episode listeners will…

1. Risk stratify patients with febrile neutropenia to inform initial diagnostic and treatment decisions
2. Choose appropriate empiric antibiotic therapy and determine duration of therapy
3. Develop strategies to inform the management of persistent febrile neutropenia

Disclosures

Dr Seo reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

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.