Guideline sources The following summarized guidelines for the evaluation and management of febrile neutropenia (FN) are prepared by our editorial team based on guidelines from the American Society of Clinical Oncology (ASCO 2023; 2018), the Infectious Diseases Society of America (IDSA/ASCO 2018), the European Society of Medical Oncology (ESMO 2016), and the Infectious Diseases Society of America (IDSA 2011). 1 2 3 4 5 6 6 6 6 Definition FN is a common consequence of cancer chemotherapy characterized by fever and underlying infection. 6 Epidemiology FN is caused by antineoplastic therapy (side-effect leading to myelosuppression or mucositis) in cancer patients. 6 Disease course Clinical manifestations of FN include fever, underlying infection associated with bacteremia, sepsis, hemodynamic instability, and death. 6 Prognosis and risk of recurrence https://web.pathway.md/diseases/recf47ynJ22uvcc9p 1/10 6/29/23, 4:02 AM Febrile neutropenia Pathway The 30-day mortality associated with FN ranges from 6% to 10%. 6 Calculator Calculator Calculat Clinical Index of Stable Febrile N Diagnostic criteria for febrile ne MASCC Guidelines 1. Screening and diagnosis Indications for screening: Assess the risk of FN (in consultation with infectious disease specialists as needed) systematically, taking into account the following factors: Situation Guidance Advanced age Patient-related factors Performance status Nutritional status Prior episode of FN Comorbidities Cancer diagnosis Cancer-related factors Cancer stage Remission status Cancer treatment response Cytotoxic regimen Treatment-related factors Dose intensity Degree and duration of gastrointestinal and/or oral mucositis Degree and duration of cytopenia. B Diagnostic criteria: As per ASCO 2018 guidelines, define fever in patients with neutropenia as a single oral temperature of 38.3 C (101 F) or a temperature of 38.0 C (100.4 F) sustained over a 1-hour period. Show 2 more As per IDSA 2011 guidelines: Define fever as a single oral temperature measurement of 38.3 C (101 F) or a temperature of 38.0 C (100.4 F) sustained over a 1-hour period. Define neutropenia as an absolute neutrophil count of < 500/ L or an absolute neutrophil count expected to decrease to < 500/ L during the next 48 hours. https://web.pathway.md/diseases/recf47ynJ22uvcc9p 2/10 6/29/23, 4:02 AM Febrile neutropenia Pathway 2. Classification and risk stratification Risk assessment (general principles): assess the risk of severe infectious complications as part of the initial evaluation of patients with FN. B Show 2 more Risk assessment, scores: As per ASCO 2018 guidelines: Use a validated predictive tool, such as the MASCC score or the Talcott's rules, to identify patients with FN eligible for outpatient management. B Consider using the CISNE as an additional tool to determine the risk of major complications in clinically stable patients with solid tumors after mild-to-moderate-intensity chemotherapy, assuming proximity to an appropriate medical facility able to provide 24- hour access. C As per ESMO 2016 guidelines, use a validated predictive tool, such as the MASCC score, to assess the risk of complications in patients with FN. A As per IDSA 2011 guidelines, consider obtaining formal risk stratification using the MASCC scoring system in patients with FN. B 3. Diagnostic investigations Clinical assessment: assume that fever in a patient with neutropenia from cancer therapy is the result of an infection in the absence of an alternative explanation. Attempt to establish clinical and microbiologic diagnoses that may affect antibacterial choice and prognosis. B Show 2 more Routine laboratory tests: Obtain the following laboratory tests as part of the initial evaluation of patients with FN: CBC with differential leukocyte and platelet count serum electrolytes, creatinine, BUN, and lactate liver biochemical tests, including TBIL, ALP, and transaminases. B Microbiological cultures: Obtain at least 2 sets of blood cultures from different anatomic sites (including a peripheral site and the lumen of a central venous catheter, if present) in patients with FN. B Obtain cultures from other sites (such as urine, lower respiratory tract, CSF, stool, or wounds) as clinically indicated. B Respiratory virus testing: Obtain a nasopharyngeal swab for the detection of influenza virus in patients with influenza- like illness, as evidenced by sudden onset of a respiratory illness characterized by fever, cough, and 1 of the following: malaise, sore throat, coryza, arthralgias, or myalgias. B Consider obtaining an expanded viral panel for the detection of additional respiratory viruses (such as influenza virus, parainfluenza virus, adenovirus, coronavirus, RSV, human metapneumovirus, enteroviruses, rhinovirus) in patients with symptoms of a respiratory viral illness in the setting of hematologic malignancy or hematopoietic stem cell transplant. C https://web.pathway.md/diseases/recf47ynJ22uvcc9p 3/10 6/29/23, 4:02 AM Febrile neutropenia Pathway Chest imaging: obtain chest imaging in patients with signs and/or symptoms of lower respiratory tract infection. B 4. Medical management Setting of care, outpatient: As per ASCO 2018 guidelines, use clinical judgment when selecting candidates for outpatient management. B As per ESMO 2016 guidelines, offer outpatient management in patients with FN at low risk of complications, if adequate follow-up is available. A As per IDSA 2011 guidelines, consider offering outpatient management in carefully selected patients with FN at low risk of complications. B Setting of care, inpatient: As per ASCO 2018 guidelines: Assess patients for admission to the hospital if any of the following occur: fever not resolving after 2-3 days of an initial, empirical, broad-spectrum antibiotic regimen fever recurring after a period of defervescence new signs or symptoms of infection use of oral medications is no longer possible or tolerable change in the empirical regimen or an additional antimicrobial drug becomes necessary microbiologic tests identify species not susceptible to the initial regimen. B Consider assessing low-risk outpatients with FN not defervescing after 2-3 days of an initial, empirical, broad-spectrum antibiotic regimen for admission to the hospital. C As per ESMO 2016 guidelines, hospitalize all patients with FN at high risk of complications. A As per IDSA 2011 guidelines, hospitalize all patients with FN at high risk of complications, if they are not already inpatients. B Show 3 more Setting of care (discharge): Ensure that patients with FN eligible for discharge and outpatient management also meet the following psychosocial and logistic requirements: residence 1 hour or 48 km ( 30 miles) from clinic or hospital primary care physician or oncologist agrees to outpatient management ability to comply with logistic requirements, including frequent clinic visits presence of family member or caregiver at home 24 hours/day access to a telephone and transportation 24 hours/day no history of noncompliance with treatment protocols. B Obtain monitoring as follows in outpatients with FN: frequent evaluation for at least 3 days in a clinic or at home daily or frequent telephone contact to verify by home thermometry that the fever resolves https://web.pathway.md/diseases/recf47ynJ22uvcc9p 4/10 6/29/23, 4:02 AM Febrile neutropenia Pathway monitoring of absolute neutrophil count and platelet count for myeloid reconstitution frequent return visits to the clinic. B Antibiotic therapy, low-risk patients: As per ASCO 2018 guidelines, administer the first dose of empiric antibiotic therapy in the clinic, emergency department, or hospital department, after fever has been documented and pretreatment blood samples have been collected, in patients with FN eligible for outpatient management. B Show 2 more As per ESMO 2016 guidelines: Initiate oral empirical therapy in low-risk patients, including patients with anticipated brief ( 7 days duration) neutropenic periods or no or few comorbidities. B Consider initiating oral and/or outpatient empirical antibiotic therapy in carefully selected low-risk patients. B As per IDSA 2011 guidelines, administer initial oral or IV empirical antibiotic doses in low-risk patients in a clinic or hospital setting. Consider transitioning to outpatient oral or IV treatment if they meet specific clinical criteria. A Show 2 more Antibiotic therapy (high-risk patients): initiate monotherapy with an anti-pseudomonal - lactam agent (such as cefepime), a carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam for IV empirical antibiotic therapy in high-risk patients with FN. A Show 5 more Antibiotic therapy (modifications): guide modifications to the initial antibiotic regimen based on clinical and microbiologic data. B Show 7 more Antibiotic therapy (duration): continue appropriate antibiotics for at least the duration of neutropenia, until the absolute neutrophil count is 500/ L, or longer if indicated according to the particular organism and site of infection. B Show 2 more Antifungal therapy (low-risk patients): do not administer empirical antifungal therapy routinely in low-risk patients, as the risk of invasive fungal infection is low. D Antifungal therapy (high-risk patients): initiate empirical antifungal therapy and investigate for invasive fungal infections in patients with persistent or recurrent fever after 4-7 days of antibiotic therapy, if the duration of neutropenia is expected to be > 7 days. A Show 3 more Antiviral therapy: administer neuraminidase inhibitors in patients with influenza virus infection, if the infecting strain is susceptible. B Show 3 more Granulocyte colony-stimulating factors: do not use G-CSFs for the treatment of established FN. D 5. Specific circumstances https://web.pathway.md/diseases/recf47ynJ22uvcc9p 5/10 6/29/23, 4:02 AM Febrile neutropenia Pathway Pediatric patients (risk assessment): adopt a validated risk stratification strategy and incorporate it into routine clinical management. B Show 2 more Pediatric patients (diagnostic evaluation): obtain blood cultures at the onset of FN from all lumens of central venous catheters. B Consider obtaining peripheral blood cultures concurrent with central venous catheter cultures. B Show 5 more Pediatric patients (antibiotic therapy, low-risk patients): Consider offering initial or step-down outpatient management if the infrastructure is in place to ensure careful monitoring and follow-up. C Consider initiating oral antibacterial therapy if the patient is able to reliably tolerate this route of administration. C Pediatric patients (antibiotic therapy, high-risk patients): Initiate monotherapy with an anti-pseudomonal -lactam, a fourth-generation cephalosporin, or a carbapenem as empiric antibacterial therapy in pediatric high-risk FN. A Reserve the addition of a second anti-Gram-negative agent or a glycopeptide for clinically unstable patients with suspected resistant infection, or for centers with a high rate of resistant pathogens. B Pediatric patients (antibiotic therapy, modification and discontinuation): discontinue double coverage for Gram-negative infection or empiric glycopeptide (if initiated) after 24-72 hours in patients responding to initial empiric antibacterial therapy, if there is no specific microbiologic indication to continue combination therapy. B Show 4 more Pediatric patients (antifungal therapy, biomarkers): Avoid obtaining serum galactomannan to guide empiric antifungal management for prolonged FN ( 96 hours) in patients at high risk for invasive fungal disease. D Do not obtain -D-glucan or fungal PCR testing in blood to guide empiric antifungal management for prolonged FN ( 96 hours) in patients at high risk for invasive fungal disease. D Pediatric patients (antifungal therapy, low-risk patients): consider withholding empiric antifungal therapy in patients at low risk for invasive fungal disease with prolonged ( 96 hours) fever and neutropenia. C Pediatric patients (antifungal therapy, high-risk patients): Administer caspofungin or liposomal amphotericin B for empiric antifungal therapy, unless a preemptive antifungal therapy approach is chosen, in patients at high risk for invasive fungal disease with prolonged ( 96 hours) FN unresponsive to broad-spectrum antibacterial therapy. A Consider implementing a preemptive antifungal therapy approach by deferring empiric antifungal therapy and initiating antifungal therapy only if evaluation suggests or indicates invasive fungal disease in non-HSCT patients at high risk for invasive fungal disease not receiving anti-mold prophylaxis with prolonged ( 96 hours) FN unresponsive to broad- spectrum antibacterial therapy. C https://web.pathway.md/diseases/recf47ynJ22uvcc9p 6/10 6/29/23, 4:02 AM Febrile neutropenia Pathway Patients with central venous catheters: exercise hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine during central venous catheter insertion for all central venous catheter insertions. A Show 5 more 6. Preventative measures Infection prevention: As per ASCO 2018 guidelines: Ensure that all healthcare workers comply with hand hygiene and respiratory hygiene/cough etiquette guidelines to reduce the risk for aerosol- and direct or indirect contact-based transmission of pathogenic microorganisms in the healthcare setting. B Advise outpatients with neutropenia from cancer therapy to avoid prolonged contact with environments that have high concentrations of airborne fungal spores (such as construction and demolition sites, intensive exposure to soil through gardening or digging, or household renovation). B As per IDSA 2011 guidelines, follow proper hand hygiene to prevent transmission of infection in the hospital. B Show 4 more Influenza vaccination: As per ASCO 2018 guidelines, provide yearly influenza vaccination with an inactivated vaccine in all patients receiving chemotherapy for malignancy and all family and household contacts and healthcare providers. B As per IDSA 2011 guidelines: Provide yearly influenza immunization with an inactivated influenza vaccine in all patients being treated for cancer. B Consider immunizing patients between chemotherapy cycles, > 7 days after the last treatment, or > 2 weeks before chemotherapy starts, in order to maximize the serologic response to immunization. C Antibiotic prophylaxis: As per ASCO 2018 guidelines: Administer antibiotic prophylaxis with a fluoroquinolone in patients at high risk for FN or profound, protracted neutropenia (most patients with acute myeloid leukemia/myelodysplastic syndromes or HSCT recipients treated with myeloablative conditioning regimens). Do not administer antibiotic prophylaxis routinely in patients with solid tumors. B Administer antimicrobial prophylaxis wutg TMP-SMX in patients receiving chemotherapy regimens associated with > 3.5% risk for pneumonia from P. jirovecii (such as containing 20 mg prednisone equivalents daily for 1 month or purine analogs). A As per IDSA 2011 guidelines, consider administering fluoroquinolone (levofloxacin or ciprofloxacin) prophylaxis in high-risk patients with expected prolonged and profound neutropenia (absolute neutrophil count 100/ L for > 7 days). B Show 3 more https://web.pathway.md/diseases/recf47ynJ22uvcc9p 7/10 6/29/23, 4:02 AM Febrile neutropenia Pathway Antifungal prophylaxis: As per ASCO 2018 guidelines, administer antifungal prophylaxis with an oral triazole or parenteral echinocandin in patients at risk for profound, protracted neutropenia (most patients with acute myeloid leukemia/myelodysplastic syndrome or HSCT recipients). Do not administer antifungal prophylaxis routinely in patients with solid tumors. B As per IDSA 2011 guidelines, administer antifungal prophylaxis with fluconazole, itraconazole, voriconazole, posaconazole, micafungin, or caspofungin against Candida infection in patients with a substantial risk of invasive candidal infection (such as allogeneic HSCT recipients or patients undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia). A Show 3 more Antiviral prophylaxis: As per ASCO 2018 guidelines: Administer antiviral prophylaxis with a nucleoside analog (such as acyclovir) in HSV- seropositive patients undergoing allogeneic HSCT or leukemia induction therapy. A Administer treatment with a nucleoside reverse transcription inhibitor (such as entecavir or tenofovir) in patients at high risk of HBV reactivation. B As per IDSA 2011 guidelines, administer antiviral prophylaxis with acyclovir against HSV in HSV-seropositive patients undergoing allogeneic HSCT or leukemia induction therapy. A Granulocyte colony-stimulating factors: As per ESMO 2016 guidelines, administer G-CSF to prevent FN in patients > 60 years of age, patients with serious comorbidities, or receiving chemotherapy regimens with a high risk (> 20%) of FN. A As per IDSA 2011 guidelines, consider administering G-CSFs to prevent FN in patients with an anticipated risk of FN 20%. B Clinical findings Symptoms Past medical history Abdominal pain BMT Anal pain Exposure to chemotherapy Burning on urination Exposure to radiation therapy Chills Human immunodeficiency virus infection Cough Immunocompromising condition Diarrhea Leukemia Dysuria Lymphoma Fever Multiple myeloma Mouth sores Sore throat Respiratory exam Sweating Toothache Dyspnea Vaginal itching Hematological findings https://web.pathway.md/diseases/recf47ynJ22uvcc9p 8/10 6/29/23, 4:02 AM Febrile neutropenia Pathway blood leukocyte count Vital signs blood neutrophil count HR body temperature systolic BP Gynecologic exam Studies 2022 SHORT In adult patients who had fever of unknown origin during high-risk neutropenia and were treated for hematological malignancy, short treatment was noninferior to extended treatment with respect to carbapenem -sensitive infection or recurrent fever. Nick A de Jonge et al. Lancet Haematol. 2022 Jun 9. References 1. Randy A Taplitz, Erin B Kennedy, Eric J Bow 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 May 10;36 14 1443 1453. Open 2. Klastersky J, de Naurois J, Rolston K et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(suppl 5):v111-v118. Open 3. 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. Open 4. Thomas Lehrnbecher, Paula D Robinson, Roland A Ammann et al. Guideline for the Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients: 2023 Update. J Clin Oncol. 2023 Jan 23;JCO2202224. Open 5. Randy A Taplitz, Erin B Kennedy, Eric J Bow et al. Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol. 2018 Oct 20;36 30 3043 3054. Open 6. Fatemeh Karimi, Farzaneh Ashrafi, Azadeh Moghaddas et al. Management of Febrile Neutropenia: A Description of Clinical and Microbiological Findings by Focusing on Risk Factors and Pitfalls. J Res Pharm Pract. 2018 Jul-Sep; 7 3 147 156. Open 7. American Society of Clinical Oncology. Choosing Wisely ASCO recommendations. Choosing Wisely. 2012. Open 8. Crawford J, Becker PS, Armitage JO et al. Myeloid Growth Factors, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017 Dec;15 12 1520 1541. Open 9. Almarie Uys, Bernardo L Rapoport, Ronald Anderson. Febrile neutropenia: a prospective study to validate the Multinational Association of Supportive Care of Cancer MASCC risk-index score. Support Care Cancer. 2004 Aug;12 8 555 60. Open https://web.pathway.md/diseases/recf47ynJ22uvcc9p 9/10 6/29/23, 4:02 AM Febrile neutropenia Pathway 10. Nick A de Jonge, Jonne J Sikkens, Sonja Zweegman et al. Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial. Lancet Haematol. 2022 Jun 9;S2352 3026 22 00145 4. Open 11. Kochanek M, Schalk E, von Bergwelt-Baildon M et al. Management of sepsis in neutropenic cancer patients: 2018 guidelines from the Infectious Diseases Working Party AGIHO and Intensive Care Working Party (iCHOP of the German Society of Hematology and Medical Oncology DGHO . Ann Hematol. 2019 May;98 5 1051 1069. Open 12. Thomas Lehrnbecher, Paula Robinson, Brian Fisher et al. Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update. J Clin Oncol. 2017 Jun 20;35 18 2082 2094. Open 13. Thomas J Smith, Kari Bohlke, Gary H Lyman 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. Open https://web.pathway.md/diseases/recf47ynJ22uvcc9p 10/10