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  • Physician

Neutropenic fever

Summary

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.

Definition

  • Neutropenia: ANC < 500/μL OR expected to decrease to < 500/μL 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]

Diagnostics

The diagnostic workup should be guided by the pre-test 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.

Laboratory studies

Imaging [1]

  • CXR for patients with respiratory symptoms
  • Further imaging (e.g., CT) should be guided by history and clinical findings.
  • See also “Focused diagnostics” and “Differential diagnoses by affected system” in fever.

Risk assessment

  • 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 should be used to 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.

MASCC score [3]

  • Standardized and validated tool for evaluating risk in patients with neutropenic fever
  • Interpretation
    • MASCC score < 21: high risk of serious medical complications and death
    • MASCC score ≥ 21: low risk of serious medical complications
Patient characteristics Points
Clinical burden of symptoms
  • 5 = mild
  • 3 = moderate
  • 0 = severe
Absence of hypotension
  • 5
Absence of COPD
  • 4
Solid tumor or hematologic malignancy with no previous fungal infection
  • 4
Absence of severe dehydration
  • 3
Patient status when fever occurred
  • 3 = outpatient
  • 0 = inpatient
Age < 60 years
  • 2

In general, any patient who does not strictly fulfill the criteria for being at low risk should be treated as a high-risk patient.

Common bacterial pathogens in neutropenic fever

Common bacterial pathogens in neutropenic fever [1]
Gram-positive
Gram-negative

Treatment

  • Empiric antibiotic therapy should be initiated immediately after two sets of blood cultures have been obtained
  • Low-risk patients who can tolerate oral intake and have a caregiver, telephone, and access to transportation may be treated with oral antibiotics on an outpatient basis.
  • High-risk patients require admission and broad-spectrum IV antibiotics to avoid sepsis and life-threatening complications
  • Once the patient is clinically stable and/or a source has been determined, consider narrowing antibiotics
  • If fever persists, reassess for fungal or viral infection and adapt treatment accordingly.

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

Empiric antibiotic therapy for neutropenic fever

Low-risk patients (MASCC ≥ 21) [1][4][5]

Recommended empiric regimen
No penicillin allergy and not taking fluoroquinolone prophylaxis

Penicillin allergy and not taking fluoroquinolone prophylaxis

Taking fluoroquinolone prophylaxis
  • No longer low-risk, proceed to high-risk recommendations.

High-risk patients (MASCC score < 21) [1][4][5]

Recommended empiric regimen
No penicillin allergy
Penicillin allergy and not taking fluoroquinolone prophylaxis
Penicillin allergy and taking fluoroquinolone prophylaxis

Suspected necrotizing or intraabdominal infection

Risk factors for MRSA

and/or a complication associated with a high risk of MRSA 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.

Fluoroquinolones should only be considered for treatment in patients not previously taking a fluoroquinolone for prophylaxis. If the patient develops a neutropenic fever while on a fluoroquinolone, they should be treated as high-risk and started on an antipseudomonal beta-lactam.

Empiric antifungal therapy for neutropenic fever [1][4]

Additional considerations

  • 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]

Supportive care

Acute management checklist

  • Identify and treat sepsis.
  • Peripheral and central blood cultures x 2 sets
  • 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
  • Parenteral fluid resuscitation and electrolyte replacement
  • Antipyretic therapy
  • Pain management
  • Pulse oximetry monitoring
  • Supplemental oxygen (if hypoxic)
  • Urinary catheter removal and replacement (if applicable)
  • Consider the removal of indwelling intravascular catheters.
  • Isolation precautions (e.g., no plants in the room, visitors wear face masks, good hand hygiene)
  • Hematology/oncology and infectious disease consultation
  • ICU transfer if hemodynamically unstable
  • 1. Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011; 52(4): pp. e56–93. doi: 10.1093/cid/cir073.
  • 2. Baden LR, Bensinger W, Angarone M, et al. Prevention and treatment of cancer-related infections. J Natl Compr Canc Netw. 2012; 10(11): pp. 1412–45. pmid: 23138169.
  • 3. Klastersky et al. The Multinational Association for Supportive Care in Cancer Risk Index: A Multinational Scoring System for Identifying Low-Risk Febrile Neutropenic Cancer Patients. Journal of Clinical Oncology. 2000; 18(16): pp. 3038–3051. doi: 10.1200/jco.2000.18.16.3038.
  • 4. Villafuerte-Gutierrez et al. Treatment of febrile neutropenia and prophylaxis in hematologic malignancies: a critical review and update. Advances in hematology. 2014; 2014: p. 986938. doi: 10.1155/2014/986938.
  • 5. Taplitz et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. Journal of Clinical Oncology. 2018; 36(14): pp. 1443–1453. doi: 10.1200/jco.2017.77.6211.
  • 6. Sandri AM, Landersdorfer CB, Jacob J, et al. Population Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients: Implications for Selection of Dosage Regimens. Clinical Infectious Diseases. 2013; 57(4): pp. 524–531. doi: 10.1093/cid/cit334.
  • 7. Bucaneve et al. Results of a Multicenter, Controlled, Randomized Clinical Trial Evaluating the Combination of Piperacillin/Tazobactam and Tigecycline in High-Risk Hematologic Patients With Cancer With Febrile Neutropenia. Journal of Clinical Oncology. 2014; 32(14): pp. 1463–1471. doi: 10.1200/jco.2013.51.6963.
  • Herold G. Internal Medicine. Cologne, Germany: Herold G; 2014.
  • Flowers et al. Communicating Safe Outpatient Management of Fever and Neutropenia. Journal of Oncology Practice. 2013; 9(4): pp. 207–210. doi: 10.1200/jop.2012.000815.
  • Flowers et al. Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology. 2013; 31(6): pp. 794–810. doi: 10.1200/jco.2012.45.8661.
last updated 04/01/2020
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