19. Neutropenic Fever

Definition

Fever occurring in a patient with ANC <500, most commonly after chemotherapy, where fever is defined as a single temperature value of ≥38.3 or ≥38.0 for ≥1 hour.

Differential Diagnosis

  • A specific pathogen is identified less than 50% of the time.
  • When identified, the pathogen is often enteric, having translocated into the blood following chemotherapy-induced mucositis.
  • In patients who remain febrile for >96 hours despite IV antibiotics, particularly if they have been neutropenic for extended periods, fungal pathogens become more common.

Evaluation

  • Careful physical exam, particularly of any indwelling lines and for rashes, can often help identify the etiology of the infection. Routine digital rectal examinations should be avoided although the rectal area should be visually inspected and one digital examination done if indicated.
  • Obtain blood culture x 2 (include central line if present) and site-specific workup as indicated by symptoms (e.g. sputum Gram stain and culture and RVP if respiratory symptoms, C. difficile toxin if diarrhea or recent antibiotic use). Obtain CXR and urinalysis (UCx if abnormal or symptoms/catheter present) in most patients.
  • Low threshold to LP if altered mental status and/or headache. CT chest if pulmonary symptoms or abnormal chest x-ray, consider CT chest if severe presentation or high risk of complications by MASCC or CISNE score. CT abdomen/pelvis (IV and PO contrast) if abdominal pain or diarrhea.

Management

  • Febrile neutropenia after chemotherapy (not bone marrow transplant):
    • Most patients with febrile neutropenia require hospitalization for IV antibiotics and monitoring. However, outpatient management may be carefully considered for patients who are young, without co-morbidities, and with short expected duration of neutropenia. Risk stratification with the MASCC and CISNE scores can be helpful. If planning to treat outpatient, care should be coordinated closely with outpatient oncologist and a safe discharge plan ensured with close follow-up.
    • Median time to defervescence after antibiotics is 2 days in patients with solid tumors.
    • Antibiotics: guidelines recommend starting antibiotics within 60 minutes of ED triage.
      • If hemodynamically stable, start therapy to cover gram-negative organisms including pseudomonas (e.g. cefepime). Add vancomycin to cover gram-positive organisms after examining patient if you suspect SSTI, central line infection, bacterial PNA, or if there is a history of MRSA infection.
      • If hemodynamically unstable, can start empiric vancomycin and cefepime. Can discontinue vancomycin once cultures negative for 48 hours. If remains unstable, consider switching cefepime to broader coverage (e.g. meropenem).
      • If site-specific infection suspected, tailor antibiotic regimen appropriately (e.g. consider atypical coverage and empiric flu treatment for pneumonia, anaerobic coverage for GI source).
      • If fever >96 hours despite empiric therapy, consider fungal infection and adding voriconazole, though fungal infections are rare in patients with solid tumors. In general, do not broaden antibiotics before this time for persistent fever in clinically stable patients. Ensure source control has been achieved (e.g. no abscess to drain).
      • Switch to linezolid for presumed VRE if enterococcus is identified, sensitivities not yet known, and patient not clinically improving on vancomycin.
      • If documented pseudomonal infection, consider adding a second agent (“double-cover”) such as an aminoglycoside or preferably fluoroquinolone if severely ill or not improving.
    • Colony stimulating factors: consider filgrastim for patients with fever and profound neutropenia (ANC <100), age >65, expected prolonged neutropenia (>10 days), documented PNA, severe presentation (e.g. sepsis), hospitalization at the time of fever onset, invasive fungal infection, or uncontrolled cancer.
  • Febrile neutropenia post-bone marrow transplant: guidelines above still apply.
    • Median time to defervescence after antibiotics is 5 days in patients with hematologic malignancies.
    • Antibiotics: most hospitals that have a bone marrow transplant unit have an antibiotic algorithm that you should follow when treating these patients. Rationale is similar to above, usually start with broad gram negative agent with anti-pseudomonal coverage (e.g. cefepime).
    • Order neutropenic precautions (no rectal exams, no flowers, no fruit), no outside food, mouth care with salt and soda rinses BID.
    • Antimicrobial prophylaxis: most patients post-bone marrow transplant will receive fluoroquinolone prophylaxis until neutrophil recovery. Broadening to an IV gram negative agent with anti-pseudomonal coverage (e.g. cefepime) is the first step if such a patient develops a fever.
    • Colony stimulating factors (filgrastim and related compounds) are commonly used after bone marrow transplant to facilitate faster engraftment, so patients who develop febrile neutropenia may already be receiving them. Management should be discussed with the malignant hematology service attending, but in general these agents may be continued through a febrile episode. However, if GVHD is suspected, management may be more nuanced.

Key Points

  • Early and aggressive treatment, particularly of gram negative bacteria, is essential.
  • For patients who are persistently febrile, follow institutional protocols for escalating antibiotics and initiation of anti-fungal therapy.
  • Consider the possibility that there may be an abscess that must be drained.

 

Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005;353:988-998.

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):e56‐e93.

Gafter-Gvili A, Fraser A, Paul M, et al. 2005 Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients.  Ann Intern Med 2005;142:979-995.

NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors Version 2.2013, 08/2013

Smith TJ, Bolkye K, Lyman GH et al. Recommendations for the use of WBC growth factors: American Society of Clinial Oncology clinical guideline update.” J Clin Oncol; 2015; 33(28): 3199-3212.