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febrile neutropenia

Febrile neutropenia is a medical emergency Classification: - high risk: - neutropenia for >= 7 days - absolute neutrophil count < 100/uL &/or - comorbidities: hypotension, pneumonia, abdominal pain, neurologic signs - low risk: - anticipated neutropenia < 7 days - few or no comorbidities Etiology: 1) typhlitis (necrotizing enterocolitis) 2) infection with encapsulated organisms in asplenic patients a) Streptococcus pneumonia b) Neisseria meningitidis c) Haemophilus influenza 3) Pseudomonas sepsis [6] 4) angioinvasive aspergillosis in leukemia patients on long-term antibiotics Epidemiology: - chemotherapy: 10% of solid tumors; 80% of hematologic malignancies [5] Clinical manifestations: - a single temperature > 38.3 C (101.0 F) or 38.0 C (100.4 F) for > 1 hour Laboratory: 1) complete blood count (CBC) with differential - absolute neutrophil count < 500/uL; < 1000/uL [1] 2) liver function tests 3) renal function tests 4) blood cultures 5) lumbar puncture with CSF analysis a) high index of suspicion only b) low risk of bleeding Radiology: 1) chest X-ray 2) computed tomography (CT) of thorax - only if chest X-ray is abnormal or if cough & tachypnea 3) abdominal CT if typhilitis (necrotizing enterocolitis) is suspected in a patient with RLQ abdominal pain [1] Complications: - ecthyma gangrenosum especially in patients with Pseudomonas sepsis [6] Management: 1) risk stratification - hospitalization, unless - no significant comorbidities (pneumonia, hypotension) - neutropenia expected to resolve within 7 days - residence < 1 hour (30 miles) from hospital - ability to comply in medical instructions - family member or caregiver at home 24 hours/day - all patients should receive IV antibiotics within 1 hour of triage - after observation for 4 hours, low-risk patients may be discharged with oral antibiotics [4,5] - oral antibiotics should cover Pseudomonas - ciprofloxacin + Augmentin [1] 2) culturing of body fluids 3) pathogens a) gram negative aerobic bacteria b) penicillin-resistant viridans Streptococci: ARDS c) fungi in patients with neutropenia > 7-10 days - Candida krusei - Candida glabrata - Candida parapsilosis - Aspergillus 4) empiric intravenous (IV) antibiotics for hospitalized patients a) first line agents (should cover Pseudomonas) - cefepime - ceftazidime - piperacillin-tazobactam (Zosyn) [1] - imipenem cilastatin - addition of aminoglycoside to beta-lactam antibiotic of no benefit & potential harm [1] - history penicillin allergy characterized by mild non-puritic rash is not a contraindication to use of cephalosporin or 3rd generation penicillin [7] - aztreonam not recommended due to lack of gram-positive coverage [7] b) vancomycin or linezolid should be added within 48 h - if patient fails to respond to initial therapy - if gram positive cocci are cultured from blood - high risk for gram positive infection (intravascular catheter) - discontinue in 3 days if use not supported by positive culture c) linezolid or daptomycin for suspected vancomycin-resistant enterococci d) metronidazole or clindamycin should be added for: - perirectal abscess - odontogenic infection - severe, acute abdominal pain suggesting typhlitis e) empiric therapy for fungal infections in patients who fail antibacterial therapy after 3-7 days - amphotericin B is drug of choice - itraconazole is alternative f) antibiotic therapy should be continued 7 days after - cultures are negative - signs of infection are gone - neutrophil count rises above 500/uL - 7 days of therapy adequate for gram-negative sepsis & neutropenia due to hematologic malignancy or hematopoietic stem cell transplantation [8] g) stop antibiotics if - cultures never positive - no source of infection identified - temperature normal for 48 hours, & - neutrophil count > 500/uL h) antiviral only if clinical or laboratory evidence of viral infection 5 supportive therapy - may be treated as outpatient if no significant comorbidities & with reliable home care [1] - indications for filgrastim (G-CSF) or GM-CSF - absolute neurophil count < 100/uL expected to last > 10 days - routine use of filgrastim not indicated [1] - prophylactic use of G-CSF or GM-CSF if high risk of febrile neutropenia [1] - start filgrastim (G-CSF) on day 2 of next cycle of chemotherapy [1] - continue full dose of chemotherapy unless overwise indicated [1]

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neutropenia

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 14, 16, 17, 18, 19. American College of Physicians, Philadelphia 2006, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  2. Paul M, Yahav D, Bivas A, Fraser A, Leibovici L. Anti-pseudomonal beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta-lactams. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD005197 PMID: 21069685
  3. Paul M, Yahav D, Fraser A, Leibovici L. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2006 Feb;57(2):176-89 PMID: 16344285
  4. Baugh CW et al. ED management of patients with febrile neutropenia: Guideline concordant or overly aggressive? Acad Emerg Med 2016 Sep 9; PMID: 27611638
  5. Bergstrom C, Nagalla S, Gupta, A. Management of Patients With Febrile Neutropenia. A Teachable Moment. JAMA Intern Med. Published online Feb 12, 2018 PMID: 29435575 https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2672206
  6. NEJM Knowledge+ Dermatology
  7. NEJM Knowledge+ Complex Medical Care
  8. Ranganath N et al. Evaluating antimicrobial duration for Gram-negative bacteremia in patients with neutropenia due to hematologic malignancy or hematopoietic stem cell transplantation. Transpl Infect Dis 2023 Jun 6; [e-pub]. PMID: 37279240 https://onlinelibrary.wiley.com/doi/10.1111/tid.14085
  9. Zimmer AJ, Freifeld AG. Optimal management of neutropenic fever in patients with cancer. J Oncol Pract. 2019;15:19-24. PMID: 30629902