Neutropenic fever is an oncologic emergency common in patients receiving chemotherapy. A decrease in a patient's absolute neutrophil count (ANC) can lead to potentially life-threatening infections, and the risk of serious infection is directly associated with the extent and duration of neutropenia. Because the immune response is impaired in neutropenia, symptoms can be mild and even a low-grade temperature (38°C) should be considered a fever. Initial workup should consist of peripheral and, if applicable, central line blood cultures; further investigation is guided by localization of clinical signs. Empiric antibiotic therapy should be started within the first hour of onset to minimize mortality risk. Treatment should be adjusted as soon as further findings are available.
See also “Fever.”
- Low ANC: typically results from cancer therapy; see “Neutropenia” for other causes of low ANC.
Source of fever
- Suspected infection (most common): can be bacterial, viral, or fungal in origin depending on the patient's risk factors, exposures, and local microbiology
- See also “Differential diagnosis of fever by course”, “Differential diagnoses of fever by affected system”, and “Differential diagnoses of fever based on associated finding” for other causes of fever.
|Common bacterial pathogens in neutropenic fever |
Recommendations in this article are consistent with the 2010 Infectious Disease Society of America (IDSA) guidelines for antibiotic therapy in neutropenic fever and the 2018 IDSA and American Society of Clinical Oncology (ASCO) guidelines for the outpatient management of neutropenic fever. 
- Start upon clinical evaluation.
- , e.g., using the . 
- Establish IV access and obtain blood cultures and routine diagnostic studies: See “Diagnostics.”
- Start blood cultures have been obtained.  as soon as two sets of
- Consult the patient's oncologist and, when appropriate, infectious disease specialists.
- Provide supportive care, e.g., IV fluids, antipyretics, pain management, antiemetics
- Admit to the hospital for treatment.
- Consider ICU level of care for patients who are hemodynamically unstable or need .
- Give broad-spectrum IV antibiotics to avoid sepsis and life-threatening complications.
- Consider narrowing antibiotics once the patient is clinically stable and a source of infection has been determined.
- Consider the need for .
- If fever persists after 4–7 days, reassess for fungal or viral infection and adapt treatment accordingly.
- Low-risk patients: Consider outpatient oral antibiotics if oral intake is tolerated and there is adequate access to a caregiver, telephone, and transportation (see “Outpatient therapy for neutropenic fever” for details).
- There are several methods of assessing risk of mortality in patients with neutropenic fever, including evaluating clinical risk factors and using a validated risk assessment tool.
- Risk assessment can help determine appropriate clinical therapy (e.g., high-risk patients should be treated as inpatients with IV antibiotics, while select low-risk patients may be considered for outpatient therapy).
Clinical risk assessment in patients with neutropenic fever 
The presence of even one high-risk feature is enough to consider inpatient therapy.
- Inpatient status at the time of fever onset
- Anticipated prolonged (> 7 days) neutropenia
- Profound (ANC < 100 cells/mm3) neutropenia
- Clinical instability (e.g., hypotension, altered mental status)
- Acute abdominal pain, nausea/vomiting, and/or diarrhea
- New pulmonary infiltrate and/or hypoxemia
- Intravascular catheter infection
- Hepatic insufficiency
- Renal insufficiency
- Uncontrolled cancer
- Induction chemotherapy for acute myelogenous leukemia or in preparation for allogeneic HCT
- Presence of oral and/or gastrointestinal mucositis
- Underlying chronic obstructive pulmonary disease
- Poor functional status
- Advanced age
- Alemtuzumab use 
- Low-risk features
MASCC score 
|Clinical burden of symptoms|| |
|Absence of hypotension|| |
|Absence of COPD|| |
|Solid tumor or hematologic malignancy with no previous fungal infection|| |
|Absence of severe dehydration|| |
|Patient status when fever occurred|| |
|Age < 60 years|| |
In general, any patient who does not strictly fulfill the criteria for being at low risk should be treated as a high-risk patient.
For patients with solid tumors scored as low risk according to the MASCC score, consider additionally calculating the score to determine the likelihood of complications if treated at home. 
Outpatient therapy for neutropenic fever 
- Start in low-risk patients.
- Give the first dose of antibiotics in a hospital or other monitored care setting.
- Observe the patient for at least 4 hours prior to discharge.
- Recommended follow-up
- Tailor antimicrobial therapy to culture results.
- Advise returning for hospital admission if any of the following are present:
The diagnostic workup should be guided by the pretest probability of the diagnoses under consideration. The following list includes commonly used methods for diagnosing or ruling out possible etiologies in patients with neutropenic fever. See also “ .”
Avoid rectal temperature measurement in patients with possible neutropenia because of the risk of introducing gut bacteria into the bloodstream through small tears in the perianal skin and mucosa. 
Initial investigations 
- CBC with differential
- Blood cultures (at least two sets)
- Blood glucose
- Liver chemistries
- Serum lactate
Further investigations 
Further diagnostics should be guided by clinical features and examination findings (see also “Focused diagnostics” and “Differential diagnoses by affected system” in “Fever”).
Benign ethnic neutropenia (BEN)
- Definition: a condition characterized by a decreased ANC (< 1500/mcL) in the absence of secondary causes and without an increased risk of infection 
- Most commonly occurs in individuals of African, Middle Eastern, and West Indian descent 
- Incidence: approx. 4% in the US 
- Etiology: associated with a single nucleotide polymorphism in the DARC gene on chromosome 1 
- Pathophysiology: not fully understood 
- Clinical features: asymptomatic
- Diagnostics: BEN is a diagnosis of exclusion. Secondary causes of neutropenia (e.g., recurrent infections, cytopenia, splenomegaly, lymphadenopathy) should be ruled out.
- Management: does not require treatment or additional monitoring
- Special patient subgroups: Patients with BEN should have lower ANC thresholds (e.g., > 500/mcL) for holding and discontinuing treatment with certain chemotherapeutic agents (e.g., doxorubicin) and clozapine than the general population. 
The differential diagnoses listed here are not exhaustive.
Empiric antibiotic therapy for neutropenic fever
Low-risk patients (MASCC ≥ 21) 
|Recommended empiric oral antibiotic regimens|
|No penicillin allergy and not taking fluoroquinolone prophylaxis|
|Taking fluoroquinolone prophylaxis|| |
High-risk patients (MASCC score < 21) 
Monotherapy with an antipseudomonal beta-lactam (e.g., piperacillin/tazobactam, cefepime, meropenem, or imipenem/cilastatin) is recommended for patients without penicillin allergy or risk factors for other specific infections (e.g. MRSA, VRE, ESBL organisms).
|Recommended empiric IV antibiotic regimens|
|No penicillin allergy|
|Penicillin allergy and not taking fluoroquinolone prophylaxis|
|Penicillin allergy and taking fluoroquinolone prophylaxis|
Suspected necrotizing or intraabdominal infection
|Risk factors for VRE|
|Risk factors for ESBL|
|Risk factors for CPE|
|Risk factors for a suspected infection include previous infection and colonization or treatment in a hospital with high rates of endemicity.|
Any recurrent fever should be considered a new episode of infection.
Only consider fluoroquinolones for treatment in patients not previously taking fluoroquinolones as prophylaxis. Treat patients who develop neutropenic fever while on fluoroquinolone prophylaxis as high-risk and start an antipseudomonal beta-lactam.
Empiric antifungal therapy for neutropenic fever 
- Low-risk patients: Empiric antifungal therapy is not routinely recommended.
High-risk patients: Consider empiric antifungal therapy in the following situations.
- Persistent or recurrent fever after 4 days of intravenous antibiotic therapy and expected duration of neutropenia > 7 days
- Reassessment does not yield a cause.
- Clinically unstable and suspected fungal infection (e.g., positive galactomannan, 1,3-β-d-Glucan assay, and/or imaging concerning for invasive fungal infection)
- Options for empiric antifungal therapy regimens include any of the following:
Other therapeutic measures
- Empiric antiviral treatment: only recommended for patients with clinical or laboratory evidence of active viral disease and in patients with possible influenza exposure.
- G-CSF or GM-CSF: Use is not routinely recommended. 
- Indications for indwelling catheter removal in patients with suspected CLABSI 
- Identify and treat sepsis.
- Obtain at least two sets of peripheral and central blood cultures.
- Assess risk and start appropriate empiric antibiotic therapy (within one hour).
- Consider additional diagnostic workup based on likely source.
- Identify and control the source of infection.
- Start supportive therapy as needed, e.g., antipyretics, analgesics, IV fluids.
- Urinary catheter removal and replacement (if applicable)
- Start .
- Hematology/oncology and infectious disease consultation
- ICU transfer if hemodynamically unstable