febrile%20neutropenia
FEBRILE NEUTROPENIA
Febrile neutropenia is having a fever of ≥38.3 ºC or ≥38 ºC over an hour and neutropenia that is having an absolute neutrophil count (ANC) of <500 neutrophils/mm3 or an ANC <1000 neutrophils/mm3 expected to decline to ≤500 neutrophils/mm3 over the next 48 hours.
The risk of febrile neutropenia is directly proportional to the duration and severity of neutropenia.
Fever is frequently the only indication of infection in the neutropenic patient.

Monitoring

  • Patient must be monitored closely for nonresponse, secondary infections, adverse effects and drug-resistant organisms
  • It may be necessary to change or add antibiotics as the clinical course progresses

Chemoprophylaxis

Granulocyte Colony-Stimulating Factors (G-CSFs)
  • Eg Filgrastim (biosimilars Filgrastim-aafi, Filgrastim-sndz, Tbo-filgrastim), Lenograstim, Pegfilgrastim (biosimilars Pegfilgrastim-bmez, Pegfilgrastim-cbqv, Pegfilgrastim-jmdb) 
  • Recommended as prophylaxis in patients with fever and neutropenia at high risk (>20%) for infection-associated complications or with prognostic factors for poor clinical outcome
  • May be considered in patients with intermediate risk (10-20%) if patients have ≥1 of the following: History of chemotherapy or radiotherapy, persistent neutropenia, bone marrow involvement, recent surgery, open wounds, liver impairment (bilirubin >2), renal dysfunction (creatinine clearance <50), advanced age (>65 years of age) currently undergoing high-intensity chemotherapy
  • Should not be used in febrile neutropenia patients with prior treatment of long-lasting prophylactic Pegfilgrastim
  • It was shown to reduce the risk of febrile neutropenia by at least 50% in patients with solid tumors without significant effect on tumor response or overall survival
  • Can also be used in patients with decreased bone marrow reserve due to extensive radiotherapy or in patients who are neutropenic due to HIV
  • Primary prophylaxis with Filgrastim or Pegfilgrastim has shown success in recent meta-analysis of randomized controlled trials
  • Secondary prophylaxis is indicated if dose reduction is below threshold or delay of chemotherapy is undesirable
Antimicrobials
  • Antimicrobials have been used for a long time as chemoprophylaxis but it led to the emergence of resistant strains that limited its efficacy
Antibiotics
  • Fluoroquinolone prophylaxis is recommended for high-risk patients with febrile neutropenia or profound neutropenia
    • Use of fluoroquinolones is discouraged in low-risk patients
    • Should be considered in patients with >7 days expected duration of neutropenia
  • Trimethoprim/sulfamethoxazole or an oral 3rd-generation cephalosporin is alternative treatment for patients with intolerance to fluoroquinolones
  • Use of Ciprofloxacin or Levofloxacin in cancer patients undergoing intensive chemotherapy have been recommended based on recent update of the Cochrane meta-analysis
Antifungals
  • Recommended for patients at intermediate and high risk for febrile neutropenia or profound/protracted neutropenia
  • Pneumocystis pneumonia (PCP) prophylaxis may be considered for intermediate to high risk patients with history of allogeneic HCT, autologous HCT, or those with acute lymphocytic leukemia (ALL)
    • Recommended antipneumocystic prophylactic agents include Trimethoprim/sulfamethoxazole (preferred), Atovaquone, Dapsone, or Pentamidine
  • Recommended antifungal prophylactic agents based on disease for patients at intermediate- to high risk for infection include:
    • ALL: Fluconazole or Micafungin (or any echinocandin); alternative agent includes Amphotericin B
    • Myelodysplastic syndrome or acute myeloid leukemia (AML): Posaconazole; alternative agents include Voriconazole, Fluconazole, Micafungin or Amphotericin B
    • Autologous HCT with mucositis: Fluconazole or Micafungin (or any echinocandin)
    • Allogeneic HCT: Fluconazole or Micafungin (or any echinocandin); alternative agents include Posaconazole, Voriconazole or Amphotericin B
    • Graft-versus-host disease (GVHD): Posaconazole; alternative agents include Voriconazole, any echinocandin, or Amphotericin B
Antivirals
  • Patients at intermediate- to high-risk for infection may be given antiviral prophylaxis (Acyclovir, Famciclovir, Valacyclovir) for herpes simplex and varicella during active therapy
    • Patients with lymphoma, multiple myeloma, CLL, or history of autologous HCT or purine analog therapy at intermediate risk for infection may be given prophylaxis against herpes simplex virus (HSV) during active therapy or longer depending on degree of immunosuppression, and may consider varicella zoster virus (VZV) prophylaxis for at least 6-12 months after autologous HCT
    • For patients with acute leukemia at high risk for infections, HSV prophylaxis may be considered
    • Patients at high risk for infections may be given prophylaxis against VZV during active proteosome inhibitor therapy
    • Patients with history of Alemtuzumab therapy, allogeneic HCT, or GVHD that required corticosteroid use, HSV prophylaxis may also be considered for a minimum of 2 months after Alemtuzumab therapy and until CD4 is ≥200 cells/mcL, or VZV prophylaxis for at least 1 year after allogeneic HCT
  • Primary prophylaxis with Letermovir may be considered in allogeneic HCT recipients at high risk for cytomegalovirus (CMV) reactivation or disease
    • Once CMV reactivation has been detected, may initiate preemptive therapy with Valganciclovir or Ganciclovir
      • For patients intolerant or unresponsive to Ganciclovir therapy, Foscarnet or Cidofovir may be considered
  • Prophylaxis using nucleoside reverse transcriptase inhibitor Entecavir (preferred) or Tenofovir (preferred) or Lamivudine should be considered in patients at high risk for hepatitis B reactivation
Vaccination
  • The use of an inactivated influenza and pneumococcal vaccines for all cancer patients with active disease or undergoing chemotherapy should be considered
  • Serogroup B meningococcal vaccination should be considered in patients at increased risk for meningococcal disease
  • Human papillomavirus vaccine is recommended for patients <26 years old, and may be considered in patients >26-≤45 years of age
  • Other recommended inactivated vaccines include H influenzae type b (Hib), hepatitis A, hepatitis B and poliovaccine to be given 6-12 months after HCT
    • Recombinant zoster vaccine is recommended 50-70 days after autologous HCT and may be considered after allogeneic HCT
  • Live vaccines such as MMR, varicella and zoster vaccine may be considered ≥24 months after HCT if patient is negative for GVHD or ongoing immunosuppression and seronegative for respective disease

Follow Up

  • Patient should be re-evaluated for hospital admission after 2-3 days of empiric broad-spectrum antibiotic therapy if with presence of any of the following:
    • Persistent fever despite 2-3 days intake of empiric broad-spectrum antibiotics
    • Fever re-occurs after period of defervescence
    • New signs and symptoms of infection occurs
    • Oral therapy is no longer tolerated
    • Additional antimicrobials or a change in the treatment regimen is needed
    • Test results showed new causative agent not covered by present antimicrobial regimen
  • Re-admission is recommended should fever persist or recur or new signs of infection appear within 48 hours
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