By: Daniel Minter
As you lay down to sleep after a long (but rewarding!) day on the ID consult service, your pager goes off. “40F with neutropenic fever- recs?” You call back and find out that the patient has a recent diagnosis of AML and is admitted for induction chemotherapy prior to anticipated allogeneic stem cell transplant. She’s been febrile for the past four days despite cefepime. The overnight resident is asking whether she should broaden the patient’s antimicrobial coverage.
Background
Fever and neutropenia is a common medical emergency requiring infectious diseases evaluation. In patients with hematologic malignancies undergoing chemotherapy, > 80% may develop febrile neutropenia (FN) during treatment. Although many episodes may simply resolve with empiric antimicrobial therapy with no etiologic agent identified, FN can also be a harbinger for serious infectious syndromes including bacteremias and invasive fungal infections. As such, having an approach to this clinical problem is important for the budding infectious diseases fellow.
Evaluation
Major components of the evaluation of a patient with FN include performing a risk stratification, identifying the syndrome, and evaluating for the possibility of invasive fungal infection (IFI).
The 2010 guidelines distinguish between high-risk and low-risk patients with FN, with the level of risk determining the need for inpatient and IV therapies. Generally speaking, factors associated with higher risk of complications include anticipated prolonged (i.e., > 7 days) and severe neutropenia (i.e., ANC < 100) as well as comorbid conditions. These tend to be patients with hematologic malignancies rather than those with solid tumors. Clinical prediction tools like the MASCC score can be employed, but much of this will rely on clinician judgment. See this curbsiders episode for a great discussion of risk stratification in FN.
A variety of distinct syndromes can cause FN, and identifying the syndrome can have major implications for empiric therapy. Specific conditions to evaluate for include central line associated infections (CLABSI, tunnel site infections), pneumonias, skin and soft tissue infections, and IFIs (see below). Many FN episodes, however, will be nonlocalizing and no etiologic syndrome will be identified.
Generally speaking, IFI should be considered (and empirically treated for) in patients with persistent fever after 4-7 days of antibiotics who have an anticipated prolonged duration of neutropenia.
Initial workup
In addition to a physical exam, an initial workup for all patients with FN should include baseline labs and at least two sets of blood cultures (culturing from each lumen of the CVC if present). IDSA guidelines recommend that cultures from other sites (e.g., urine) and chest radiography be obtained as clinically indicated. It should be noted however, that neutropenic patients with pulmonary infections may have minimal respiratory symptoms and chest x-ray findings can be minimal or absent.
In those who are persistently febrile despite appropriate antibiotics, an aggressive workup to determine the source should be undertaken. Additional testing to consider at this point could include cross sectional imaging (e.g., CT chest, sinus, abdomen/pelvis) as well as consideration for noninvasive fungal biomarkers (e.g., beta-D glucan and galactomannan).
Treatment considerations
For high-risk patients with FN, guidelines recommend upfront use of an intravenous antibacterial agent with broad spectrum gram-positive, gram-negative, and antipseudomonal coverage (e.g., pip/tazo, cefepime, a carbapenem). The rationale for this comes from epidemiologic studies showing that the range of pathogens involved in FN has shifted from gram-negative bacilli (including pseudomonas) to more gram-positive organisms (Staphylococcus, Streptococcus, Enterococcus) in recent years. Vancomycin is only required if the syndrome suggests severe sepsis with hemodynamic instability, blood cultures with a gram-positive bacteria (prior to final speciation), a hospital-acquired pneumonia, central line infection, SSTI, or severe mucositis in patients receiving fluoroquinolone prophylaxis lacking strep activity (e.g., ciprofloxacin) and receiving ceftazidime (which has less gram-positive coverage).
Empiric antifungal coverage can be considered in certain high-risk patients who have fevers that persist or recur for 4-7 days despite appropriate empiric therapy. This should ideally be paired with an expanded diagnostic workup.
Take homes:
- Risk stratify patients with FN
- Perform a basic infectious workup in all patients with FN
- Empiric therapy with a broad spectrum antipseudomonal agent is recommended for all high-risk patients
- Vancomycin should be added in certain circumstances that increase the likelihood of MRSA
- Empiric antifungal therapy should be considered for patients in whom fever persists or recurs at 4-7 days despite appropriate therapy
Updated 8/26/22