Neutropenic Fever

Get CMENeutropenic Fever in ChildrenWe all are well aware of the prevalence “fever” as a presenting complaint. We are also well aware that not all “cc: fever” are created equal. Fever in a neonate may be due to a virus, but we can’t bet on it. Fever in the patient with delayed cap refill requires more contemplation than what is the maximum dose of antipyretic. Fever in a patient with sickle cell disease warrants special attention. While, generally, I have a disdain for making medical decisions based heavily on the WBC count (“WBC count is the Last Bastion of the Intellectually Destitute” – Dr. Amal Mattu @amalmattu), there are conditions that mandate respect for the WBC, like leukemia and childhood cancers. Let us take a minute to review the current recommendations for initial management of Neutropenic Fever:

 

Neutropenic Fever: Basics

  • Neutropenia definitions can vary between institutions. [White, 2014]
    • Typical definition = Absolute Neutrophil Count (ANC) < 1500 cell/microL
    • Severe neutropenia is ANC < 500
  • Patients receiving chemotherapy are at high risk for morbidity and mortality due to infections! [Cohen, 2016]
    • The reduced immune system may lead these patients to present with limited or atypical signs of illness.
    • Fever may be the only sign of significant infection.
  • Neutropenic fever is one of the most common and serious complications that occurs during chemotherapy. [Lehrnbecher, 2017;Klastersky, 2016]

 

Low vs High Risk?

  • There are a number of scoring systems used to assess a patient’s risk of bacteremia and morbidity/mortality. [Lehrnbecher, 2017]
  • None of them are universally agreed upon. [Lehrnbecher, 2017; Cohen, 2016]
    • There are 6 clinically based low-risk stratification strategies.
    • All still require local validation. [Lehrnbecher, 2017]
  • Factors known to increase risk:
    • Chemotherapeutic regimen
    • Advanced disease or progressive disease
    • AML, ALL, Burkitt lymphoma, and relapsed acute leukemia
    • History of hematopoietic stem-cell transplantation
    • History of prior febrile neutropenia
    • Use of high dose corticosteroids
    • Presence of a focal site of infection (ex, pneumonia, abscess)
    • Presence of central venous access
    • Mucositis
    • Absolute Monocyte Count <100/microL

 

Neutropenic Fever: ED Evaluation

  • While signs and symptoms may be minimal, there presence is important!
  • Search for:
    • Complaints of chills or rigors
    • Hypotension
    • Poor Perfusion
    • A Source!
      • Mucositis
      • Abscess
      • Pulmonary
      • Urinary tract
      • GI tract
      • Perineal region infection
      • Necrotizing Fasciitis (localized pain out of proportion) [Johnston, 2001]
      • CNS infection
    • Don’t skimp on the labs!
      • CBC with differential (obviously, need this to confirm neutropenia)
      • Blood cultures
        • From all lumens of central line
        • May also obtain peripheral culture as this can increase the detection of true bacteremia by 12%, but must be weighed against risk of contamination and pain. [Lehrnbecher, 2017]
      • Cultures of other potential sources
      • Urinalysis and Urine Culture, even if asymptomatic [Lehrnbecher, 2017; Sandoval, 2012]
      • Basic electrolyte panel
      • Chest Xray only for patients with pulmonary signs/symptoms. [Lehrnbecher, 2017; Roberts, 2012]

 

Neutropenic Fever: Initial Management

  • DON’T JUST WAIT, RESUSCITATE!
    • Again, being aware that chemotherapy may lead to subtle presentations, the patient/family may not become alert to illness until the child is much sicker.
    • IV or IO boluses fluids if perfusion is poor or hypotension present.
    • Empiric broad spectrum dual therapy antibiotics
      • Antipseudomonal Beta-Lactam, 4th generation cephalosporin, or carbapenem PLUS a second gram-negative agent or a glycopeptide for the clinically unstable is recommended. [Lehrnbecher, 2017]
      • Dual coverage is also recommended if a resistant infection is suspected. [Lehrnbecher, 2017]
      • Ex: Cefepime AND Aminoglycoside AND Vancomycin
      • Tailor to the patient’s prior culture results and hospital resistance patterns
    • Early use of pressors if need be.
  • IF THE CHILD LOOKS WELL, DON’T BE CAVALIER!
    • Again, presentation can be subtle in these patients with non-functioning immune systems.
    • Having a institutional protocol for evaluation and management of pediatric neutropenic fever can help expedite care and decrease time to antibiotic administration. [Cohen, 2016; Cash, 2014]
    • Obtain labs, including cultures and give empiric antibiotics.
      • If the child looks well, then empiric mono-therapy is recommended. [Lehrnbecher, 2017; Chuang, 2002]
      • If there is a documented neutropenia in the last 24 hours, treat empirically with monotherapy antibiotics (ex, Cefepime).
      • Due to the high incidence of infections with patients presenting with neutropenic fever, some advocate for giving empiric antibiotics even prior to confirmation of neutropenia in patients with: [Cohen, 2016]
        • Active Chemotherapy regimens (or off less than 1 month) OR
        • History of congenital or acquired neutropenia not related to chemo.
      • Some children will be able to go home on oral antibiotics, but this will be contingent upon assessment of being “low risk” with the Oncologist. [Lehrnbecher, 2017]

 

Moral of the Morsel

  • Don’t be fooled. The patient with no immune system deserves significant respect and requires our vigilance.
  • Be thorough.Where is the source? Look at the mucous membranes and consider necrotizing fasciitis (i.e., look in the perineum)!
  • Be aggressive! If the child looks sick, throw all of the antibiotics at them. If the child looks well, mono-therapy is recommended.
  • High Risk vs Low Risk… don’t decide alone. Your physical exam and lab results will help determine whether a patient is high risk or low risk, but that determination should be made concurrently with the patient’s oncologist.

 

References

Lehrnbecher T1, Robinson P1, Fisher B1, Alexander S1, Ammann RA1, Beauchemin M1, Carlesse F1, Groll AH1, Haeusler GM1, Santolaya M1, Steinbach WJ1, Castagnola E1, Davis BL1, Dupuis LL1, Gaur AH1, Tissing WJE1, Zaoutis T1, Phillips R1, Sung L1. Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update. J Clin Oncol. 2017 May 1:JCO2016717017. PMID: 28459614. [PubMed] [Read by QxMD]

Cohen C1, King A, Lin CP, Friedman GK, Monroe K, Kutny M. Protocol for Reducing Time to Antibiotics in Pediatric Patients Presenting to an Emergency Department With Fever and Neutropenia: Efficacy and Barriers. Pediatr Emerg Care. 2016 Nov;32(11):739-745. PMID: 25822237. [PubMed] [Read by QxMD]

Klastersky J1, de Naurois J2, Rolston K3, Rapoport B4, Maschmeyer G5, Aapro M6, Herrstedt J7; ESMO Guidelines Committee. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016 Sep;27(suppl 5):v111-v118. PMID: 27664247. [PubMed] [Read by QxMD]
Cash T1, Deloach T, Graham J, Shirm S, Mian A. Standardized process used in the emergency department for pediatric oncology patients with fever and neutropenia improves time to the first dose of antibiotics. Pediatr Emerg Care. 2014 Feb;30(2):91-3. PMID: 24457498. [PubMed] [Read by QxMD]

Rosenblum J1, Lin J, Kim M, Levy AS. Repeating blood cultures in neutropenic children with persistent fevers when the initial blood culture is negative. Pediatr Blood Cancer. 2013 Jun;60(6):923-7. PMID: 23047811. [PubMed] [Read by QxMD]

Sandoval C1, Sinaki B, Weiss R, Munoz J, Ozkaynak MF, Tugal O, Jayabose S. Urinary tract infections in pediatric oncology patients with fever and neutropenia. Pediatr Hematol Oncol. 2012 Feb;29(1):68-72. PMID: 22304012. [PubMed] [Read by QxMD]

Roberts SD1, Wells GM, Gandhi NM, York NR, Maron G, Razzouk B, Hayden RT, Kaste SC, Shenep JL. Diagnostic value of routine chest radiography in febrile, neutropenic children for early detection of pneumonia and mould infections. Support Care Cancer. 2012 Oct;20(10):2589-94. PMID: 22278307. [PubMed] [Read by QxMD]

Maertens JA1, Madero L, Reilly AF, Lehrnbecher T, Groll AH, Jafri HS, Green M, Nania JJ, Bourque MR, Wise BA, Strohmaier KM, Taylor AF, Kartsonis NA, Chow JW, Arndt CA, DePauw BE, Walsh TJ; Caspofungin Pediatric Study Group. A randomized, double-blind, multicenter study of caspofungin versus liposomal amphotericin B for empiric antifungal therapy in pediatric patients with persistent fever and neutropenia. Pediatr Infect Dis J. 2010 May;29(5):415-20. PMID: 20431381. [PubMed] [Read by QxMD]

Meckler G1, Lindemulder S. Fever and neutropenia in pediatric patients with cancer. Emerg Med Clin North Am. 2009 Aug;27(3):525-44. PMID: 19646652. [PubMed] [Read by QxMD]

Mendes AV1, Sapolnik R, Mendonça N. New guidelines for the clinical management of febrile neutropenia and sepsis in pediatric oncology patients. J Pediatr (Rio J). 2007 May;83(2 Suppl):S54-63. PMID: 17530138. [PubMed] [Read by QxMD]

Wananukul S1, Nuchprayoon I, Siripanich H. Mucocutaneous findings in febrile neutropenic children with acute leukemias. J Med Assoc Thai. 2005 Jun;88(6):817-23. PMID: 16083222. [PubMed] [Read by QxMD]

Chuang YY1, Hung IJ, Yang CP, Jaing TH, Lin TY, Huang YC. Cefepime versus ceftazidime as empiric monotherapy for fever and neutropenia in children with cancer. Pediatr Infect Dis J. 2002 Mar;21(3):203-9. PMID: 12005083. [PubMed] [Read by QxMD]

Johnston DL1, Waldhausen JH, Park JR. Deep soft tissue infections in the neutropenic pediatric oncology patient. J Pediatr Hematol Oncol. 2001 Oct;23(7):443-7. PMID: 11878579. [PubMed] [Read by QxMD]

Sean Fox

I enjoy taking care of patients and I finding it endlessly rewarding to help train others to do the same. I trained at the Combined Emergency Medicine and Pediatrics residency program at University of Maryland, where I had the tremendous fortune of learning from world renown educators and clinicians. Now I have the unbelievable honor of working with an unbelievably gifted group of practitioners at Carolinas Medical Center. I strive every day to inspire my residents as much as they inspire me.

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