Febrile neutropenia

Last reviewed: 22 Feb 2023

Last updated: 13 Dec 2022

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

More key diagnostic factors

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

Other diagnostic factors

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

More risk factors

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

More 1st investigations to order

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

More investigations to consider

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

Associate 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.

Differentials
- Drug fever
- Tumour fever
- Thromboembolism
More Differentials
Guidelines
- NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infections
- NCCN clinical practice guidelines in oncology: hematopoietic growth factors
More Guidelines
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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

Differentials

Guidelines

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