Sarah Klemencic, MD; Jack Perkins, MD


Western J Emerg Med. 2019;20(2):316-322. 

In This Article

Neutropenic Fever

Neutropenic fever (NF) is one of the most well-known oncologic emergencies. Up to 80% of patients receiving chemotherapy for hematologic malignancies will develop NF at least once during the course of therapy.[1–3] Patients with solid tumors are reported to develop NF at a rate of 10–50% during the course of chemotherapy.[1–3] The likelihood of fever increases with the duration and the severity of neutropenia as well as the rate of decline of the absolute neutrophil count (ANC).[4] The ANC nadir is often 7–10 days after the conclusion of chemotherapy.[5] NF is defined as a single oral or axillary temperature of ≥ 38.3°Celsius (C) (101°Fahrenheit [F]) or a temperature ≥ 38.0°C (100.4°F) sustained over 60 minutes in a patient with an ANC < 500/μL (microliter).[5] Neutropenia can be characterized as mild, moderate, severe, or profound (Table 1).[5,6]

While EPs should be most concerned with bacterial etiologies of NF, it is actually uncommon for a definite etiology to be determined for an episode of NF.[7,8] Only 20–35% of episodes of NF are due to a clinically documented infection (i.e., source identified by culture, antigens, or other testing modalities).[2–4,7–8] This should be expected since NF may be due to the underlying malignancy itself (e.g., leukemia), mucositis, toxicity of the chemotherapeutic agents, or a host of other etiologies.[2,3] If a bacterial source is the culprit, it is most likely to be endogenous flora from the gut (e.g., Escherichia coli, Enterobacter), skin (e.g., Staphylococcus, Streptococcus), or respiratory tract (e.g., Streptococcus).[2–4,7–8] The past few decades have seen a change in the bacterial epidemiology associated with NF. Gram-positive bacterial infections (e.g., Staphylococcus, Streptococcus) have become at least as likely as gram-negative infections (e.g., Escherichia coli, Pseudomonas) due to a rising incidence of indwelling catheters and a higher community burden of Staphylococcus.[2–4,7–9] Additionally, the incidence of Clostridium difficile (C. diff) and resistant gram-negative pathogens is increasing.[10] A fungal etiology is unlikely if it is the patient's first episode of NF; however, this risk increases if the patient is taking empiric antibiotics, receiving total parenteral nutrition, or has concurrent mucositis.[11]

Once a patient is identified as having NF, it is incumbent upon the EP to proceed systematically in terms of diagnostic evaluation, antibiotic administration, and disposition. Standard initial testing should include a complete blood count (CBC) with manual differential, complete metabolic panel (CMP), two sets of blood cultures (including one from an indwelling line if applicable), urinalysis and culture, and chest radiograph (CXR) (two views preferred).[5] If the patient has diarrhea, consider adding stool cultures and C. diff testing. Keep in mind that in the winter influenza testing should be regarded as standard for NF evaluation. It is important to keep in mind that the neutropenic patient will not be able to mount a robust inflammatory response, and thus the sensitivity of a CXR will decrease.[12–14]

Broad-spectrum antibiotics should be administered within 60 minutes once NF is identified and appropriate cultures have been obtained.[5,15–16] The choice of empiric antibiotic (e.g., cefepime, meropenem) will vary based on the institution according to the local antibiogram. Refer to Table 2 for common empiric regimens for NF.[17–22]

Empiric coverage for gram-positive organisms (e.g., vancomycin) is indicated in patients who are hypotensive, have a skin and soft tissue source, are currently taking a fluoroquinolone or trimethoprim/sulfamethoxazole, or who have an indwelling line.[5] While NF is most certainly a medical emergency requiring timely source assessment and delivery of broad-spectrum antibiotics, it is no longer standard to admit all NF patients to the hospital.[23–26] In fact, recent literature suggests that EPs are not familiar with the most recent NF guidelines both in terms of antibiotic deployment (i.e., when vancomycin is recommended) and disposition.[23–24] Much as in other diseases seen in EM, a continuum exists in NF such that some patients will be at much higher risk of developing sepsis and its related morbidity and mortality.

Any decision on disposition of the NF patient should be made in conjunction with the patient's oncologist or the on-call oncologist. Even if the patient is clearly in need of admission, early oncology input is essential as they may well have pertinent clinical information that is not available in the electronic medical record regarding prior episodes of NF for that patient, current chemotherapy regimen and side effects, and potential for more unusual pathogens (e.g., fungal, viral, parasitic).[26] While all NF patients were commonly admitted in the past, disposition of patients with NF is no longer straightforward as not all patients may require admission to the inpatient setting.[26] In addition to the cost and resource utilization (i.e., occupied inpatient bed) associated with an inpatient stay, there is risk to the patient with neutropenia in being admitted to the hospital with subsequent exposure to nosocomial pathogens.[27] Any NF patient with sepsis requires admission to the hospital as do those patients with significant co-morbid illness (e.g., congestive heart failure, chronic obstructive pulmonary disease) or an unstable social situation precluding reliable follow up.[24–26] Select patients (i.e., not septic, no major co-morbid illness, stable social situation) may be suitable for outpatient management of NF. Most experts recommend using the Multinational Association for Supportive Care in Cancer score (MASCC) for assisting with disposition decisions (Table 3).[28]

It is important to note that a higher MASCC score is associated with better outcomes. Scores ≥ 21 are considered "low risk" and these patients may be suitable for outpatient management.[28] In the past few years, a new scoring system referred to as CISNE (Clinical Index of Stable Febrile Neutropenia – see Table 4)[29] has been developed, and early literature comparing MASCC and CISNE has been promising in terms of equivalence.[30–31] However, it is important to note that the clinical practice guidelines were developed before CISNE was validated, and use of this tool should be considered with consultation from the patient's oncologist.