Febrile neutropenia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Last reviewed: 11 Jun 2025

Last updated: 28 Nov 2024

Febrile neutropenia is the most common life-threatening complication of cancer therapy; its treatment is an oncological emergency.

Prompt empirical antibiotic therapy has dramatically improved outcomes and decreased mortality from febrile neutropenia.

Selecting the optimal agent(s) for empirical therapy is critical and should take into account local and regional antibiotic resistance patterns, individual patient history, and presenting signs and symptoms in association with fever

A causative organism is only identified in approximately one third of patients with febrile neutropenia.

Due to a decreased ability to mount an inflammatory response, many patients with febrile neutropenia related to a deep-seated focus of infection fail to demonstrate typical localising signs or symptoms.

Prophylactic antibiotics at the onset of neutropenia can decrease fever and bloodstream infection events in high-risk patients. However, use of prophylaxis requires careful risk-benefit assessment and close monitoring for the emergence of antibiotic resistance and antibiotic-associated adverse effects or toxicity.

Definition

Febrile neutropenia is the presence of fever in a neutropenic patient. It is the most common life-threatening complication of cancer therapy and is considered an oncological emergency.

Febrile neutropenia is defined as a single oral temperature measurement of >38.3ºC (>101ºF) or a temperature of ≥38.0ºC (≥100.4ºF) sustained over 1 hour, with an absolute neutrophil count (ANC) of <500 cells/microlitre, or an ANC that is expected to decrease to <500 cells/microlitre over the next 48 hours.[1]

Patients at high risk for medical complications are those with anticipated duration of severe neutropenia (ANC <500 cells/microlitre) for >7 days. Various scoring systems (e.g., Talcott score, Multinational Association of Supportive Care in Cancer [MASCC] score, and Clinical Index of Stable Febrile Neutropenia [CISNE] score) have been proposed to classify risk for serious complications based on age, comorbidities, vital signs and laboratory results at presentation, and the presence of mucositis.[2][3][4]

History and exam

Key diagnostic factors

recent chemotherapy
fever

Full details

Other diagnostic factors

age >65 years
immunosuppressive therapy
prior chemotherapy-induced neutropenia
low performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] >1)
haematological malignancies
advanced-stage disease
prior antibiotic regimens
low albumin (<35 g/L [<3.5 g/dL])
elevated bilirubin and liver enzymes (aspartate aminotransferase and alkaline phosphatase)
pre-existing organ dysfunction and comorbid conditions
low first-cycle nadir absolute neutrophil count (<500 cells/microlitre)
signs of pneumonia (cough, abnormal breath sounds, shortness of breath)
abdominal pain
nausea or vomiting
diarrhoea
skin erythema, warmth, tenderness
mucositis or oral ulcers
infection, inflammation, or ulceration of genital and anal area
infected indwelling catheters
pyuria
chemoradiotherapy
recent historical features and exposures
sinus tenderness

Full details

Risk factors

age >65 years
haematological malignancies
low albumin (<35 g/L [<3.5 g/dL])
elevated bilirubin
elevated liver enzymes
pre-existing organ dysfunction and comorbid conditions
recent chemotherapy
low first-cycle nadir absolute neutrophil count (<500 cells/microlitre)
chemoradiotherapy
prior chemotherapy-induced neutropenia
female sex
low performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] >1)
advanced-stage disease
immunosuppressive therapy

Full details

Diagnostic investigations

1st investigations to order

FBC and differential
urinalysis and renal function tests (urea and creatinine)
liver function tests (LFTs)
blood cultures
chest x-ray

Full details

Investigations to consider

gastrointestinal pathogen molecular assay
urine culture
lumbar puncture
fungal cultures and serologies (beta-glucan and galactomannan)
viral molecular assay
echocardiogram
CT scans of the chest, abdomen, and pelvis

Full details

Treatment algorithm

ACUTE

high risk of complication or death: initial presentation

low risk of complication or death: initial presentation

ONGOING

persistent fever beyond 3-5 days of treatment

Contributors

Authors

Lynne Strasfeld, MD

Professor of Medicine

Department of Medicine, Division of Infectious Diseases

Oregon Health and Science University

Portland

Disclosures

LS declares that she has no competing interests.

Acknowledgements

Dr Lynne Strasfeld would like to gratefully acknowledge Dr Kenneth V. I. Rolston, Dr Lior Nesher, Dr Caron Jacobson, and Dr Joseph Antin, previous contributors to this topic.

Disclosures

KVIR has research grants from Merck, Shionogi, and JMI Laboratories for the performance of in vitro studies of novel antimicrobial agents. LN has given two educational lectures sponsored by MSD. CJ and JA declare that they have no competing interests.

Peer reviewers

Alison Freifeld, MD

Professor of Medicine, Infectious Diseases Division

University of Nebraska College of Medicine

Omaha

Disclosures

AF has received payment by Merck for work as an adjudication committee member for clinical trials of letermovir. AF has received an investigator-initiated study grant from Merck.

John Wingard, MD

Price Eminent Scholar and Professor of Medicine

Director

Bone Marrow Transplant Program

Division of Hematology/Oncology

University of Florida College of Medicine

Gainesville

Disclosures

JW has been reimbursed by Pfizer, Merck, Astellas, and Enzon for speaking fees, fees for educational programs, and consulting.

Matthew Falagas, MD, MSc, DSc

Director

Alfa Institute of Biomedical Sciences

Marousi

Athens

Greece

Disclosures

MF declares that he has no competing interests.

Ruth Pettengell, MBChB FRACP PhD

Senior Lecturer in Haematology

Honorary Consultant in Medical Oncology

St George's University of London

London

Disclosures

RP has received speaker fees and been reimbursed by Roche, Amgen, Chigai, and Bayer for attending several conferences. RP is a co-author of the EORTC guidelines referenced in this topic.

References

Our in-house evidence and editorial teams collaborate with international expert contributors and peer reviewers to ensure that we provide access to the most clinically relevant information possible.

Key articles

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 Feb 15;52(4):e56-93.Full text Abstract

Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015 Oct 1;33(28):3199-212.Full text Abstract

Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(5 suppl):v111-8.Full text Abstract

Taplitz RA, Kennedy EB, Bow EJ, 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. J Clin Oncol. 2018 Feb 20;36(14):1443-53.Full text Abstract

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections [internet publication].Full text

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

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Febrile neutropenia

Summary

Definition

History and exam

Key diagnostic factors

Other diagnostic factors

Risk factors

Diagnostic investigations

1st investigations to order

Investigations to consider

Treatment algorithm

high risk of complication or death: initial presentation

low risk of complication or death: initial presentation

persistent fever beyond 3-5 days of treatment

Contributors

Authors

Lynne Strasfeld, MD

Disclosures

Acknowledgements

Disclosures

Peer reviewers

Alison Freifeld, MD

Disclosures

John Wingard, MD

Disclosures

Matthew Falagas, MD, MSc, DSc

Disclosures

Ruth Pettengell, MBChB FRACP PhD

Disclosures

References

Key articles

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials

Guidelines

Log in or subscribe to access all of BMJ Best Practice

Log in or subscribe to access all of BMJ Best Practice

Log in to access all of BMJ Best Practice