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Febrile Neutropenia - StatPearls - NCBI Bookshelf
Febrile Neutropenia - StatPearls - NCBI Bookshelf
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Febrile Neutropenia
Authors
Affiliations
1 The Brooklyn Hospital Center
2 Brooklyn Hospital Center
3 Qatar University
Objectives:
Explain the importance of communication and urgency amongst the interprofessional team to improve the
outcome in patients with febrile neutropenia.
Introduction
Neutropenic fever is when there is a single oral temperature greater than or equal to 101 F (38.3 C) or a temperature
greater than or equal to 100.4 F (38 C) 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. In profound neutropenia, the
ANC is less than 100 cells/microliter.[2] The risk of bacteremia increases with profound neutropenia. To calculate
ANC, multiply the total white blood cell (WBC) count by the percentage of polymorphonuclear cells (PMNs) and
band neutrophils.[3]
Following hematological terms are commonly employed to classify abnormal neutrophil counts:
Etiology
In most cases, the infectious etiology cannot 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. 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.[4]
Most infections are bacterial, but viral or fungal etiology is possible. Common bacterial pathogens include gram-
positive bacteria infections such as Staphylococcus, Streptococcus, and Enterococcus species. Drug-resistant
organisms, including Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, Escherichia
coli, and Klebsiella species, have also been identified as infectious agents.
Congenital neutropenia: It is suspected in adults with severe neutropenia (<500 cells/microL) along with a
history of somatic findings (e.g., premature graying of the hair, pancreatic dysfunction, abnormalities of
fingernails or skeleton).
Drugs: Besides chemotherapeutic agents, the following list includes common drugs that may contribute to
neutropenia.
Antibiotics
Macrolides
Vancomycin
Chloramphenicol
Trimethoprim-sulfamethoxazole
Sulfonamides
Antimalarials
Hydroxychloroquine
Amodiaquine
Quinine
Anti-inflammatory drugs
Penicillamine
Leflunomide
Methotrexate
Gold salts
Sulfasalazine
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Psychotropic drugs
Clozapine
Phenothiazines
Propylthiouracil
Methimazole
Carbimazole
Cardiovascular drugs
Propranolol
Digoxin
Dipyridamole
Antiseizure medications
Ethosuximide
Carbamazepine
Phenytoin
Nutritional deficiency:
Severe vitamin B12, folate, or copper deficiency can also result in neutropenia.
Epidemiology
The specific frequency of agranulocytosis is unknown; It is estimated to be 1.0 to 3.4 cases per million people
annually. 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.
Gram-positive bacteria have now become the most common pathogens causing febrile neutropenia.[5] A lot of these
infections are contributed by long-term indwelling central venous catheters.[6] Although there is a slight trend toward
Gram-negative bacteria, the ratio of gram-positive to gram-negative bacteria as the cause of bacteremia in patients
with cancer is approximately 60 to 40.[7] Among gram-positive bacteria, Staphylococcus aureus (particularly
methicillin-resistant strains), enterococci (particularly vancomycin-resistant strains), and some viridans streptococci
can cause serious infections.[5]
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
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encounters an infectious pathogen. Patients lose or have weakened immunity to fend off infections in this
immunocompromised state. 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.[8] About 1% of patients undergoing chemotherapy and
radiation experience this complication.[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.[9] If diarrhea is present, a sample may be
checked. If the patients have any respiratory symptoms, a chest x-ray is necessary.
For example, Galactomannan may be performed on patient serum, or bronchoalveolar lavage samples may
serve as a diagnostic biomarker of fungal infections.
1,3-beta-D-glucan (BDG) is a fungal-specific cell wall component and may serve as a diagnostic biomarker of
fungal infections.
Procalcitonin, though still under investigation, may have moderate diagnostic accuracy for the detection of
bacteremia in patients with sepsis.[10]
Patients with unknown chest infiltrate on imaging may benefit from the culture of BAL fluid.[2]
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
risk-stratify patients into high-risk and low-risk neutropenic fever.
The MASCC was created the assess the risk of severe 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 less than 21 are high
risk.[11]
Characteristic/Score
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Type of Cancer
Solid tumor: 4
No dehydration: 4
A more specific scale for low-risk patients classification is the CISNE which may be more useful in the emergency
department setting. 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 for severe illnesses.
Characteristics/Score
Stree-induced hyperglycemia: 2
Interpretation
CISNE/Recommendation
Treatment / Management
Management is guided by whether the patients are high-risk or low-risk. Patients with the following are considered as
high risk:
Receipt of cytotoxic therapy sufficiently myelosuppressive to result in anticipated severe neutropenia (ANC
<500 cells/mcL) for >7 days
CISNE score of ≥3
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Evidence of hepatic insufficiency (aminotransferase levels >5 times normal values) or renal insufficiency
(creatinine clearance of <30 mL/minute)
In the outpatient setting, oral empiric therapy with fluoroquinolone plus amoxicillin/clavulanate is recommended in
low-risk patients. Ciprofloxacin 500-750 mg orally every 12 hours and amoxicillin/clavulanate 500 mg orally every 8
hours is a common empiric regime.
Clindamycin can be used for those with penicillin allergies. If the patient remains febrile for 48 to 72 hours, the
patient will require admission.[12]
For high-risk patients presenting with neutropenic fever, intravenous antibiotic therapy should be given within 1 hour
after triage and 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/tazobactam.[12] The usual recommended dosages are as follows:
Antipseudomonal carbapenems:
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.[13] If patients do not respond to treatments,
coverage should be expanded to include resistant species:[12][1]
Empiric antifungal coverage is advised in high-risk patients with persistent fever after 4 to 7 days of broad-spectrum
antibacterial regimen and suspicion of fungal infection.
Appropriate antibiotics may be continued until the ANC is ≥ 500 cells/mm or when the infection is cleared. If
the patients remain neutropenic after the appropriate treatment course is completed and oral fluoroquinolone
prophylaxis with the resolution of all signs and symptoms of documented infection is resumed until marrow recovery.
Antifungal prophylaxis with an oral triazole with patients with profound neutropenia
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Treatment with a nucleoside reverse transcription inhibitor is recommended for patients at high risk of hepatitis
B virus reactivation.
Herpes simplex virus- seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should
receive prophylaxis.
Patients with a ≥ 20% risk of febrile neutropenia may benefit from using colony-stimulating factors.
The National Comprehensive Cancer Network (NCCN) guidelines recommend that patients at a high risk of
neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs).[17]
Differential Diagnosis
Transfusion reaction
Tumor-related fever
Thrombophlebitis
Viral infections
Prognosis
Researchers have several prognostic factors, and there is controversy surrounding prognostic factors. Hematological
parameters, prophylactic measurements, and individual patient risk factors have yielded inconsistent results. The
MASCC risk-index score, originally designed to identify low-risk patients, showed a lower MASCC score correlated
with a poorer prognosis of febrile neutropenia. Very low levels (<15) demonstrated a high rate of complications.
Patients with severe sepsis and septic shock commonly had procalcitonin concentrations greater than 2.0
ng/ml, which merits consideration for an increased likelihood of poor prognosis.[18]
Complications
Most patients with chemotherapy-induced febrile neutropenia recover rapidly without serious complications.
However, it remains life-threatening, treatment-related toxicity and correlates with chemotherapy dose reductions and
delays in continuing chemotherapy, potentially compromising treatment outcomes, leading to shock and death.
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All staff members should have a heightened sense of urgency when interviewing patients undergoing chemotherapy
presenting with new-onset fever. As mentioned above, the pharmacist should assist the team with antibiotic selection
and dosing. The nursing staff should monitor the patient and report any concerns or changes in condition to the team.
The best outcomes are achieved by an interprofessional team approach to diagnosing and managing this life-
threatening condition. [Level 5]
Review Questions
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. Adv Hematol. 2014;2014:986938. [PMC
free article: PMC4265549] [PubMed: 25525436]
2. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard
JR., Infectious Diseases Society of America. 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. [PubMed: 21258094]
3. Rivera-Salgado D, Valverde-Muñoz K, Ávila-Agüero ML. [Febrile neutropenia in cancer patients: management in
the emergency room]. Rev Chilena Infectol. 2018;35(1):62-71. [PubMed: 29652973]
4. Hakim H, Flynn PM, Knapp KM, Srivastava DK, Gaur AH. Etiology and clinical course of febrile neutropenia in
children with cancer. J Pediatr Hematol Oncol. 2009 Sep;31(9):623-9. [PMC free article: PMC2743072]
[PubMed: 19644403]
5. Holland T, Fowler VG, Shelburne SA. Invasive gram-positive bacterial infection in cancer patients. Clin Infect
Dis. 2014 Nov 15;59 Suppl 5(Suppl 5):S331-4. [PMC free article: PMC4303051] [PubMed: 25352626]
6. Raad I, Chaftari AM. Advances in prevention and management of central line-associated bloodstream infections
in patients with cancer. Clin Infect Dis. 2014 Nov 15;59 Suppl 5:S340-3. [PubMed: 25352628]
7. Gudiol C, Bodro M, Simonetti A, Tubau F, González-Barca E, Cisnal M, Domingo-Domenech E, Jiménez L,
Carratalà J. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection
in neutropenic cancer patients. Clin Microbiol Infect. 2013 May;19(5):474-9. [PubMed: 22524597]
8. 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. Br J Haematol. 2014
Nov;167(4):441-52. [PubMed: 25196917]
9. Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, Herrstedt J., ESMO Guidelines
Committee. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016
Sep;27(suppl 5):v111-v118. [PubMed: 27664247]
10.
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Disclosure: Paul Edemobi declares no relevant financial relationships with ineligible companies.
Disclosure: Amr Elmoheen declares no relevant financial relationships with ineligible companies.
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Tables
Streptococcus
pneumoniae
Streptococcus
pyogenes
Gram-negative Bacteria
Escherichia coli Proteus spp
Pseudomonas Capnocytophaga
aeruginosa canimorsus
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