Neutropenic fever

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.”

• Neutropenia: ANC < 500/mcL OR expected to decrease to < 500/mcL within 48 hours ^[1]
• Fever: single oral temperature ≥ 38.3°C (101°F) OR ≥ 38°C (100.4°F) for at least 1 hour ^[1]

• 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.

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. ^[1][2]

Approach ^[1][2]

• All patients
  • Start neutropenia precautions upon clinical evaluation.
  • Risk stratify patients with neutropenic fever, e.g., using the MASCC score. ^[2]
  • Establish IV access and obtain blood cultures and routine diagnostic studies: See “Diagnostics.”
  • Start empiric antibiotic therapy for neutropenic fever as soon as two sets of blood cultures have been obtained. ^[3]
  • Consult the patient's oncologist and, when appropriate, infectious disease specialists.
  • Provide supportive care, e.g., IV fluids, antipyretics, pain management, antiemetics
• High-risk patients
  • Admit to the hospital for treatment.
  • Consider ICU level of care for patients who are hemodynamically unstable or need sepsis management.
  • 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 empiric fungal therapy for neutropenic fever.
  • 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).

Plan treatment for neutropenic fever in consultation with the patient's oncologist.

Neutropenic fever is an emergency! Mortality risk increases if no empiric antibiotic therapy has been initiated after one hour.

Risk stratification

• 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 ^[1]

The presence of even one high-risk feature is enough to consider inpatient therapy.

• High-risk features
  • 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 ^[4]
• Low-risk features
  • Anticipated brief (≤ 7 days) neutropenia
  • Clinical stability
  • No hepatic or renal insufficiency
  • No or few comorbidities

MASCC score ^[5]

A standardized and validated tool for evaluating risk in patients with neutropenic fever.

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 clinical index of stable febrile neutropenia score to determine the likelihood of complications if treated at home. ^[2]

Outpatient therapy for neutropenic fever ^[1][2][6]

• Start empiric antibiotic therapy for neutropenic fever 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
  • At least 3 days of symptom monitoring with frequent in-person visits
  • Daily temperature checks
  • Blood tests: regular ANC, platelet count
• Tailor antimicrobial therapy to culture results.
• Advise returning for hospital admission if any of the following are present:
  • Fever persisting despite 48–72 hours of antibiotic therapy
  • Recurrence of fever after initial improvement
  • New signs of infection
  • IV antibiotics are needed.

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 “Diagnostic evaluation for fever.”

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. ^[1]

Initial investigations ^[1][2]

• CBC with differential
• Blood cultures (at least two sets)
  • A minimum of two sets (i.e., aerobic and anaerobic bottles) should be drawn from two separate peripheral vein sites (four bottles in total).
  • If a central venous catheter is present, one set should be drawn from each lumen, and one set should be drawn from a peripheral vein. ^[2]
• BMP
  • Creatinine
  • Blood glucose
• Liver chemistries
• Serum lactate

Further investigations ^[1]

Further diagnostics should be guided by clinical features and examination findings (see also “Focused diagnostics” and “Differential diagnoses by affected system” in “Fever”).

• Laboratory studies
  • Culture from any suspected site of infection, e.g., urinalysis with urine culture , stool culture, wound culture
  • Respiratory viral panel
  • ESR/CRP
  • Procalcitonin
• Imaging
  • CXR for patients with respiratory symptoms, e.g., to look for PCP pneumonia
  • Further imaging (e.g., CT) as required

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 ^[7]
• Epidemiology
  • Most commonly occurs in individuals of African, Middle Eastern, and West Indian descent ^[8]
  • Incidence: approx. 4% in the US ^[9]
• Etiology: associated with a single nucleotide polymorphism in the DARC gene on chromosome 1 ^[10][11]
• Pathophysiology: not fully understood ^[8]
• 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. ^[12][13]

In contrast to other causes of neutropenia (e.g., neutropenic fever, systemic lupus erythematosus, sepsis), the risk of infection is not increased in BEN.

The differential diagnoses listed here are not exhaustive.

The following focuses primarily on antimicrobial therapy for presumed causes of neutropenic fever. See “Management of neutropenic fever” for a general approach.

Empiric antibiotic therapy for neutropenic fever

Antibiotics are generally continued until an appropriate treatment course is completed (usually 7–14 days depending on site of infection) and the ANC is at least 500 cells/mm³. ^[1]

Low-risk patients (MASCC ≥ 21) ^[1][2][6]

High-risk patients (MASCC score < 21) ^[1][2][6]

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).

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 ^[1][6]

• 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:
  • Caspofungin
  • Micafungin
  • Anidulafungin
  • Voriconazole
  • Amphotericin B

Give patients who received antifungal prophylaxis a different antifungal agent effective against molds (e.g., from voriconazole to amphotericin B).

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. ^[1]
• Indications for indwelling catheter removal in patients with suspected CLABSI ^[1]
  • Bacteremia with S. aureus, P. aeruginosa, fungi, or mycobacteria
  • Diagnosis of septic thrombosis
  • Tunnel or port pocket site infection
  • Endocarditis
  • Sepsis with hemodynamic instability
  • Bloodstream infection that persists despite > 72 hours of appropriate antibiotic therapy.

• 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 neutropenia precautions.
• Hematology/oncology and infectious disease consultation
• ICU transfer if hemodynamically unstable