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Febrile Neutropenia


Febrile Neutropenia

Article Author:
Sheena Punnapuzha
Article Author:
Paul Edemobi
Article Editor:
Amr Elmoheen
Updated:
3/30/2020 3:53:42 PM
For CME on this topic:
Febrile Neutropenia CME
PubMed Link:
Febrile Neutropenia

Introduction

Neutropenic fever is when there is a single oral temperature of greater than or equal to 101 F, or a temperature greater than or equal to 100.4 F for at least an hour, with an absolute neutrophilic count (ANC) of less than 1500 cells/microliter.[1] In severe neutropenia, the ANC is less than 500 per microliter or ANC that is expected to decrease below 500 cells/microL in the next 2 hours. In profound neutropenia, the ANC is less than 100 cells/microliter. To calculate ANC, multiply the total white blood cell (WBC) count by the percentage of polymorphonuclear cells (PMNs) and band neutrophils.[2]

Etiology

In the majority of cases, the infectious etiology is unable to be determined and gets marked as a fever of unknown origin (FUO). The definition of FUO is neutropenic cases with a fever greater than 38.3 C, without any clinically or microbiologically defined infection.[3][4] Documented infections only comprise approximately 30% of cases. However, infections are the primary cause of morbidity and mortality in patients with cancer who present with fever and neutropenia.[3] The majority of infections are bacterial, but viral or fungal etiology is possible.[5] Common bacterial pathogens include gram-positive bacteria infections such as Staphylococcus, Streptococcus, and Enterococcus species.[5] Drug-resistant organisms, including Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, Escherichia coli, and Klebsiella species, have also been identified as infectious agents.

Epidemiology

The specific frequency of agranulocytosis is unknown; It could be estimated to be 1.0 to 3.4 cases per million population per year. Neutropenia was particularly associated with HIV infection, acute leukemias, and myelodysplastic syndromes. Drug-induced neutropenia has an incidence of one case per million persons per year. About 50% of patients with febrile neutropenia will develop an infection, of which 20% with profound neutropenia will observe bacteremia.[6]

Pathophysiology

Neutropenic fever is the most common and serious complication associated with hematopoietic cancers or with patients receiving chemotherapeutic regimens for cancer. Neutropenic fever occurs when a neutropenic patient encounters an infectious pathogen. In this immunocompromised state, patients lose or have weakened immunity to fend off infections. The host barriers, such as the mucosal lining of the GI tract or sinuses, may be damaged, leading the host, open to invasion from an infectious pathogen.[7] About 1% of patients undergoing chemotherapy and radiation experience this complication.[8]

History and Physical

A detailed history of the patients presenting illness, chemotherapy treatment, medication use, previous history of infections, especially with bacterial resistant organisms, and the presence of allergies, should be noted to guide your therapy.[8] Signs of infection may require assessment; Pain and tenderness may be the only indicators of infection. Significant risk factors for the development of febrile neutropenia include older age, comorbidities, the specific type of cancer, and the type and number of myelosuppressive chemotherapy agents in use.[9]

Evaluation

Lab tests should be ordered; complete blood count to determine the patient's neutropenic level; blood, urinalysis, and throat cultures are needed to determine the source of infection. Two sets of blood cultures should be obtained from a peripheral vein and any venous catheters as well as specimens for testing from any sites of infection, before the immediate administration of empirical broad-spectrum antimicrobial therapy. Urinary tract infections should be suspected in asymptomatic patients with a history of such infections.[8] If diarrhea is present, a sample may be checked. If the patients have any respiratory symptoms, a chest x-ray is necessary.

 Two widely used assessment tools, The Multinational Association for Supportive Care in Cancer (MASCC) and The Clinical Index of the Stable Febrile Neutropenia (CISNE), can be part of the patient interview. These tools can help to risk-stratify patients into high risk and low-risk neutropenic fever.

The MASCC was created the assess the risk of serious complications in patients with neutropenic fever. The MAASC index has a max score of 26. Patients with a score greater than 21 are considered low risk, and patients less than 21 are high risk.[10]

MASCC Scoring Index

Characteristic/Score

  • The burden of illness: no or mild symptoms/5
  • The burden of illness: none or mild/5
  • The burden of illness: moderate symptoms/3
  • The burden of illness: severe symptoms/0
  • No hypotension (systolic BP greater than 90 mmHg)/5
  • No chronic obstructive pulmonary disease/4

Type of Cancer

  • Solid tumor/4
  • Lymphoma with previous fungal infection/4
  • Hematologic with previous fungal infection/4
  • No dehydration/4
  • Outpatient status (at the onset of fever)/3
  • Age less than 60 years/2

A more specific scale for classification of low-risk patients is the CISNE and may be more useful in the emergency department setting.[5] One of the components of the scale is the Eastern Cooperative Oncology Group (ECOG) Performance Status, which helps determines the patient’s functional status as a surrogate for the patient’s ability to undergo therapies in serious illnesses.

The Clinical Index of Stable Febrile Neutropenia Score

Characteristics/Score

  • ECOG performance status (greater than 2)/2
  • Chronic obstructive pulmonary disease (COPD)/1 
  • Stree-induced hyperglycemia/2
  • Chronic cardiovascular disease/1
  • Monocytes less than 200 per mcL/1
  • Grade greater than or equal to 2 mucositis/1
  • Interpretation

CISNE/Recommendation

  • 0-2/Consider outpatient management with oral antibiotics
  • Greater than or equal to 3/inpatient management

Treatment / Management

In low-risk patients, oral empiric therapy with a fluoroquinolone plus amoxicillin/clavulanate is recommended in the outpatient setting.[6] Clindamycin can be used for those with penicillin allergy. If the patient remains febrile for 48 to 72 hours, the patient will require admission.[5]

For high-risk patients presenting with neutropenic fever, an intravenous antibiotic therapy should be given within 1 hour after triage and be monitored more than 4 hours before discharge. The Infectious Disease Society of America (IDSA) recommends monotherapy with antipseudomonal beta-lactam agents such as cefepime, carbapenems, or piperacillin and tazobactam. [5] Vancomycin is not recommended for initial therapy but should be considered if suspecting catheter-related infection, skin or soft tissue infections pneumonia, or hemodynamic instability.[11] If patients do not respond to treatments, coverage should be expanded to include resistant species[5][1][12][13][14][13][12]:

  • Methicillin-resistant Staphylococcus aureus (MRSA): vancomycin, linezolid, and daptomycin
  • Vancomycin-resistant enterococci (VRE): linezolid and daptomycin
  • Extended-spectrum beta-lactamase (ESBL)-producing organisms: carbapenems
  • Klebsiella pneumoniae: carbapenems, polymyxin, colistin, or tigecycline

Recommendation for prevention of infection in neutropenic patients:

  • Fluoroquinolones as prophylaxis for patients who are high risk
  • Antifungal prophylaxis with an oral triazole with patients with profound neutropenia
  • Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended treatment for patients receiving chemotherapy regimens associated with greater than 3.5% risk for pneumonia from Pneumocystis jirovecii
  • Yearly influenza vaccination is recommended for all patients receiving chemotherapy
  • Treatment with a nucleoside reverse transcription inhibitor is recommended for patients who are at high risk of hepatitis B virus reactivation
  • Herpes simplex virus- seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis

In the National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that patients that are at a high risk of neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs).[15]

Differential Diagnosis

  • Transfusion reaction
  • Medication allergies and toxicities
  • Tumor-related fever

Enhancing Healthcare Team Outcomes

Febrile neutropenia is an oncological emergency that requires a team of infectious disease specialists, emergency medicine, oncology, pharmacy, and specialty-trained nurses and pharmacists for proper management, working as a collaborative interprofessional team. [Level 5] The most important determining factor of the outcomes of patients is the timing of administrating IV antibiotics.  Early admission of antibiotics has been shown to reduce mortality and the hospital length of these patients.[16][17] [Level 3] A heightened sense of urgency should be present in all staff members when interviewing with patients undergoing chemotherapy presenting with new-onset fever. The pharmacist should assist the team with antibiotic selection and dosing. The nursing staff should provide monitor of the patient and report untoward changes to the team. The best outcomes are achieved by an interprofessional team approach to the diagnosis and management of this life-threatening condition. [Level 5]


References

[1] Villafuerte-Gutierrez P,Villalon L,Losa JE,Henriquez-Camacho C, Treatment of febrile neutropenia and prophylaxis in hematologic malignancies: a critical review and update. Advances in hematology. 2014;     [PubMed PMID: 25525436]
[2] Rivera-Salgado D,Valverde-Muñoz K,Ávila-Agüero ML, [Febrile neutropenia in cancer patients: management in the emergency room]. Revista chilena de infectologia : organo oficial de la Sociedad Chilena de Infectologia. 2018;     [PubMed PMID: 29652973]
[3] Hakim H,Flynn PM,Knapp KM,Srivastava DK,Gaur AH, Etiology and clinical course of febrile neutropenia in children with cancer. Journal of pediatric hematology/oncology. 2009 Sep;     [PubMed PMID: 19644403]
[4] Yapici O,Gunseren F,Yapici H,Merdin A,Yaylali ÜÜ,Merdin FA, Evaluation of febrile neutropenic episodes in adult patients with solid tumors. Molecular and clinical oncology. 2016 Mar;     [PubMed PMID: 26998287]
[5] Lucas AJ,Olin JL,Coleman MD, Management and Preventive Measures for Febrile Neutropenia. P     [PubMed PMID: 29622943]
[6] Karimi F,Ashrafi F,Moghaddas A,Derakhshandeh A, Management of Febrile Neutropenia: A Description of Clinical and Microbiological Findings by Focusing on Risk Factors and Pitfalls. Journal of research in pharmacy practice. 2018 Jul-Sep;     [PubMed PMID: 30211240]
[7] van der Velden WJ,Herbers AH,Netea MG,Blijlevens NM, Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. British journal of haematology. 2014 Nov;     [PubMed PMID: 25196917]
[8] Klastersky J,de Naurois J,Rolston K,Rapoport B,Maschmeyer G,Aapro M,Herrstedt J, Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Annals of oncology : official journal of the European Society for Medical Oncology. 2016 Sep;     [PubMed PMID: 27664247]
[9] Fontanella C,Bolzonello S,Lederer B,Aprile G, Management of breast cancer patients with chemotherapy-induced neutropenia or febrile neutropenia. Breast care (Basel, Switzerland). 2014 Apr;     [PubMed PMID: 25404882]
[10] Ferreira JN,Correia LRBR,Oliveira RM,Watanabe SN,Possari JF,Lima AFC, Managing febrile neutropenia in adult cancer patients: an integrative review of the literature. Revista brasileira de enfermagem. 2017 Nov-Dec;     [PubMed PMID: 29160494]
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[12] Chung SJ,Miller RA,Permpalung N,Baker AW,Diehl LF,Rizzieri DA,Alexander BD, Fluoroquinolone prophylaxis reduces febrile neutropenia, bloodstream infections from mucosal translocations, and intensive care admissions in high risk hematological patients, a single center experience. Leukemia     [PubMed PMID: 30126315]
[13] Yoshida M,Ohno R, Antimicrobial prophylaxis in febrile neutropenia. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2004 Jul 15;     [PubMed PMID: 15250025]
[14] Neumann S,Krause SW,Maschmeyer G,Schiel X,von Lilienfeld-Toal M, Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors : guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Annals of hematology. 2013 Apr;     [PubMed PMID: 23412562]
[15] Hashiguchi Y,Kasai M,Fukuda T,Ichimura T,Yasui T,Sumi T, Chemotherapy-induced neutropenia and febrile neutropenia in patients with gynecologic malignancy. Anti-cancer drugs. 2015 Nov;     [PubMed PMID: 26267078]
[16] Rosa RG,Goldani LZ, Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia. Antimicrobial agents and chemotherapy. 2014 Jul;     [PubMed PMID: 24752269]
[17] Monroe K,Cohen CT,Whelan K,King A,Maloney L,Deason J,Nichols JC,Friedman GK,Kutny M,Hayes L, Quality Initiative to Improve time to Antibiotics for Febrile Pediatric Patients with Potential Neutropenia. Pediatric quality     [PubMed PMID: 30229205]