Neutropenic fever

Last updated: February 21, 2022

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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.”

  • Neutropenia: ANC < 500/mcL OR expected to decrease to < 500/mcL 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]
Common bacterial pathogens in neutropenic fever [1]
Gram-positive
Gram-negative

Recommendations in this article are consistent with the 2010 Infectious Disease Society of America (IDSA) guidelines for antibiotic therapy in neutropenic fever and the 2018 IDSA and American Society of Clinical Oncology (ASCO) guidelines for the outpatient management of neutropenic fever. [1][2]

Approach [1][2]

Plan treatment for neutropenic fever in consultation with the patient's oncologist.

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

Risk stratification

  • 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 can help 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 [5]

A standardized and validated tool for evaluating risk in patients with neutropenic fever.

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

Interpretation

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

For patients with solid tumors scored as low risk according to the MASCC score, consider additionally calculating the clinical index of stable febrile neutropenia score to determine the likelihood of complications if treated at home. [2]

Outpatient therapy for neutropenic fever [1][2][6]

The diagnostic workup should be guided by the pretest 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.”

Avoid rectal temperature measurement in patients with possible neutropenia because of the risk of introducing gut bacteria into the bloodstream through small tears in the perianal skin and mucosa. [1]

Initial investigations [1][2]

Further investigations [1]

Further diagnostics should be guided by clinical features and examination findings (see also “Focused diagnostics” and “Differential diagnoses by affected system” in “Fever”).

Benign ethnic neutropenia (BEN)

  • Definition: a condition characterized by a decreased ANC (< 1500/mcL) in the absence of secondary causes and without an increased risk of infection [7]
  • Epidemiology
    • Most commonly occurs in individuals of African, Middle Eastern, and West Indian descent [8]
    • Incidence: approx. 4% in the US [9]
  • Etiology: associated with a single nucleotide polymorphism in the DARC gene on chromosome 1 [10][11]
  • Pathophysiology: not fully understood [8]
  • Clinical features: asymptomatic
  • Diagnostics: BEN is a diagnosis of exclusion. Secondary causes of neutropenia (e.g., recurrent infections, cytopenia, splenomegaly, lymphadenopathy) should be ruled out.
  • Management: does not require treatment or additional monitoring
  • Special patient subgroups: Patients with BEN should have lower ANC thresholds (e.g., > 500/mcL) for holding and discontinuing treatment with certain chemotherapeutic agents (e.g., doxorubicin) and clozapine than the general population. [12][13]

In contrast to other causes of neutropenia (e.g., neutropenic fever, systemic lupus erythematosus, sepsis), the risk of infection is not increased in BEN.

The differential diagnoses listed here are not exhaustive.

The following focuses primarily on antimicrobial therapy for presumed causes of neutropenic fever. See “Management of neutropenic fever” for a general approach.

Empiric antibiotic therapy for neutropenic fever

Antibiotics are generally continued until an appropriate treatment course is completed (usually 7–14 days depending on site of infection) and the ANC is at least 500 cells/mm3. [1]

Low-risk patients (MASCC ≥ 21) [1][2][6]

Recommended empiric oral antibiotic regimens
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][2][6]

Monotherapy with an antipseudomonal beta-lactam (e.g., piperacillin/tazobactam, cefepime, meropenem, or imipenem/cilastatin) is recommended for patients without penicillin allergy or risk factors for other specific infections (e.g. MRSA, VRE, ESBL organisms).

Recommended empiric IV antibiotic regimens
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.

Only consider fluoroquinolones for treatment in patients not previously taking fluoroquinolones as prophylaxis. Treat patients who develop neutropenic fever while on fluoroquinolone prophylaxis as high-risk and start an antipseudomonal beta-lactam.

Empiric antifungal therapy for neutropenic fever [1][6]

Give patients who received antifungal prophylaxis a different antifungal agent effective against molds (e.g., from voriconazole to amphotericin B).

Other therapeutic measures

  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): p.e56-93. doi: 10.1093/cid/cir073 . | Open in Read by QxMD
  2. 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): p.1443-1453. doi: 10.1200/jco.2017.77.6211 . | Open in Read by QxMD
  3. 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 . | Open in Read by QxMD
  4. 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): p.524-531. doi: 10.1093/cid/cit334 . | Open in Read by QxMD
  5. 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): p.1463-1471. doi: 10.1200/jco.2013.51.6963 . | Open in Read by QxMD
  6. Rand KH, Beal SG, Rivera K, Allen B, Payton T, Lipori GP. Hourly Effect of Pretreatment With IV Antibiotics on Blood Culture Positivity Rate in Emergency Department Patients. Open Forum Infect Dis. 2019; 6 (5). doi: 10.1093/ofid/ofz179 . | Open in Read by QxMD
  7. Baden LR, Bensinger W, Angarone M, et al. Prevention and treatment of cancer-related infections.. J Natl Compr Canc Netw. 2012; 10 (11): p.1412-45.
  8. 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): p.3038-3051. doi: 10.1200/jco.2000.18.16.3038 . | Open in Read by QxMD
  9. Newburger PE, Dale DC. Evaluation and Management of Patients With Isolated Neutropenia. Semin Hematol. 2013; 50 (3): p.198-206. doi: 10.1053/j.seminhematol.2013.06.010 . | Open in Read by QxMD
  10. Atallah-Yunes SA, Ready A, Newburger PE. Benign ethnic neutropenia.. Blood Rev. 2019; 37 : p.100586. doi: 10.1016/j.blre.2019.06.003 . | Open in Read by QxMD
  11. Hsieh M, Chin K, Link B, et al. Benign Ethnic Neutropenia in Individuals of African Descent: Incidence, Granulocyte Mobilization, and Gene Expression Profiling.. Blood. 2005; 106 (11): p.3069-3069. doi: 10.1182/blood.v106.11.3069.3069 . | Open in Read by QxMD
  12. Reich D, Nalls MA, Kao WH, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene.. PLoS Genet. 2009; 5 (1): p.e1000360. doi: 10.1371/journal.pgen.1000360 . | Open in Read by QxMD
  13. Rappoport N, Simon AJ, Lev A, et al. Correlation between 'ACKR1/DARC null' polymorphism and benign neutropenia in Yemenite Jews.. Br J Haematol. 2015; 170 (6): p.892-5. doi: 10.1111/bjh.13345 . | Open in Read by QxMD
  14. Hershman D, Weinberg M, Rosner Z, et al. Ethnic neutropenia and treatment delay in African American women undergoing chemotherapy for early-stage breast cancer.. J Natl Cancer Inst. 2003; 95 (20): p.1545-8. doi: 10.1093/jnci/djg073 . | Open in Read by QxMD
  15. Manu P, Sarvaiya N, Rogozea LM, Kane JM, Correll CU. Benign Ethnic Neutropenia and Clozapine Use: A Systematic Review of the Evidence and Treatment Recommendations.. J Clin Psychiatry. 2016; 77 (7): p.e909-16. doi: 10.4088/JCP.15r10085 . | Open in Read by QxMD
  16. Flowers et al.. Communicating Safe Outpatient Management of Fever and Neutropenia. Journal of Oncology Practice. 2013; 9 (4): p.207-210. doi: 10.1200/jop.2012.000815 . | Open in Read by QxMD

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