It's Getting Hot in Here: Febrile Neutropenia

Febrile neutropenia (or Neutropenic Fever; FN/NF) is the most common life-threatening complication of cancer therapy and is often considered an oncologic emergency.

But what really is FN? And how do we manage it?

In today's article, we'll review the basics of FN, risk assessment and ways to assess the severity, and how to treat and manage this life-threatening condition.

FN is exactly what it says it is. It refers to the occurrence of a fever during a period of significant neutropenia (1). Seems simple enough, right? Let's break that down even further:

The first part consists of a fever. I'm certain that we've all experienced a fever at least once before in our lives. You're hot, sweating buckets, and you overall feel pretty crummy when you have a fever. Many of us know the specific temperature cut-point to designate a fever is 100.4 F (or 38 C). For the clinical definition of FN, one must have either (2, 3):

• A temperature of 100.4 F (38 C) for at least 1 hour, OR
• A single, oral temperature of 101 F (38.3 C) or greater

The other part consists of neutropenia. Neutropenia is a condition where the number of neutrophils (measured as Absolute Neutrophil Count [ANC]) is abnormally low. Neutrophils are a specific type of white blood cell (immune cell) that play an important role in the body's first line of defense. Depending on how low a patient's neutrophil count is, that will determine the severity of neutropenia. While current guidance may vary, in general here's the breakdown of neutropenic severity (2, 3):

• Neutropenia = ANC < 1500 or 1000 cells/mcL
• Severe neutropenia = ANC < 500 cells/mcL OR the ANC is expected to drop < 500 cells/mcL within the next 48 hours
• Profound neutropenia = ANC < 100 cells/mcL

Often times, the ANC value is automatically provided within a patient's medical chart, especially when they're admitted to a hematology/oncology unit or floor. If it's not provided, this is the equation to manually calculate the ANC:

In most FN cases, we don't actually know the true cause. If the etiology can't be determined clinically or microbiologically, it gets marked as a "fever of unknown origin" (FUO).

Infectious etiologies on the other hand only comprise of about 30% of all cases (2). Despite this low prevalence, infections are the primary cause of morbidity and morality in FN patients. Most infectious etiologies are bacterial, but viral or fungal causes are possible as well. Before we started treating with empiric therapy, some of the most frequent cases were due to gram-negative organisms (e.g., Pseudomonas spp. and Enterobacteriaceae like E. coli or Klebsiella spp.). Once we began using empiric therapy in these patients, the more common etiologic organisms became gram-positive (e.g., coagulase-negative staphylococci, Staphylococcus aureus, etc.).

Below is a table outlining the most common infectious etiologies of FN:

Infections aren't the only cause of FN. Other conditions and/or scenarios include congenital, autoimmune, bone marrow dysfunction or disorders, and of course, chemotherapy. Medications can also cause neutropenia through destruction of neutrophils or inhibiting the production of blood cells (hematopoiesis).

Below is a more comprehensive list of other etiologies including specific medications:

There are two main risk assessment tools we can use that will help determine the overall risk/severity of a patient's FN (i.e., low-risk vs. high-risk) which will eventually aid in the treatment and management. These are the Multinational Association of Supportive Care in Cancer (MASCC) Risk Index and the Clinical Index of Stable Febrile Neutropenia (CISNE) score.

The MASCC Risk Index (5) is used to identify low-risk patients (score ≥ 21) for serious complications of FN (including death, intensive care unit admission, confusion, cardiac complications, respiratory failure, renal failure, hypotension, bleeding, and other serious medical complications). It was first created in 2000 during the MASCC study, an international collaboration to derive and validate a scoring system to identify low-risk patients for complications of FN (6). It consists of several assessments that the clinician performs:

The CISNE score (7) is a more specific scale also to classify low-risk patients and may be more useful in emergency department settings. It is primarily designed for use in patients with solid tumors presenting with FN and are stable based on history and clinical examinations. The original development of CISNE was from a cohort of 861 patients with FN and subsequently validated in a multi-center study of 1133 patients (8, 9). Here is what the CISNE score consists of:

Note that the CISNE score should NOT be used in patients who are considered high-risk on initial assessment:

• Acute organ failure (cardiac, renal, respiratory)
• Have decompensation of chronic organ failure
• Are in septic shock or are hypotensive (SBP < 90 mmHg)
• Have severe infection (e.g., pneumonia, meningitis, etc.)

On top of the MASCC and CISNE scores, there are guideline-directed risk assessments from both the Infectious Diseases Society of America (IDSA) (10) and the National Comprehensive Cancer Network (NCCN) (11). Here's how they both categorize FN severity:

Notice and appreciate how both the IDSA and NCCN guidelines provide very similar risk assessment criteria for FN patients. The IDSA guidance dates back to 2010, while the NCCN guidance is newer and constantly being updated, with the last update in 2024. Take that information how you will.

Due to the life-threatening aspect of FN, it's critical that clinicians are able to determine when it's present in patients on top of the severity. Prompt empiric antibiotic therapy is necessary to avoid progression to sepsis and eventual death. Thus, in all cancer patients presenting with FN it's recommended that empiric antimicrobial therapy should be initiated immediately (at least within 60 minutes; the earlier the better) after blood cultures have been obtained and before any other investigations have been completed.

Regarding WHAT we need to treat, recall the common etiologies of infectious FN. Gram-positives make up the majority of cases of infectious FN, followed by our gram-negatives. However, even though gram-positives are more frequent, it's generally more important to cover broadly for gram-negatives due to their virulence and association with severe sepsis and worse outcomes.

For our low-risk individuals, the appropriate antibiotic regimen is based on the likelihood of infection with an antibiotic-resistant organism:

For our high-risk individuals, the appropriate antibiotic regimen is driven by multiple factors including the degree of compromise, prior infection history, local resistance patterns, and characteristics of the antibiotics chosen:

Sometimes, it may be necessary or even recommended to place patients on preventative therapy (prophylaxis) for FN. For instance, if we know that patients will be undergoing intensive cytotoxic chemotherapy regimens that are certain to reduce neutrophil levels and/or induce prolonged neutropenia, we can consider placing them on prophylaxis regimens.

There is a TON of information regarding prophylactic regimens in FN patients and we won't go through that in this article, but here is some general guidance for high-risk individuals categorized by etiology:

• Febrile neutropenia (FN) is a serious, life-threatening condition that commonly occurs in patients receiving chemotherapy. Infectious etiologies comprise of about 30% of those cases, with bacteria causing most of those cases.
• Risk assessment is a key factor in the treatment and management of individuals with FN. Once risk has been identified for the patient, timely administration of antimicrobials (within 1 hour) should be performed.
• For low-risk individuals, ciprofloxacin + Augmentin is sufficient, while in high-risk individuals it's recommended to administer an IV antibiotic such as piperacillin/tazobactam or cefepime for anti-pseudomonal coverage.
• Prevention may be provided in certain individuals receiving cytotoxic chemotherapy regimens.

1. Patel K, West HJ. Febrile Neutropenia. JAMA Oncol. 2017;3(12):1751. doi:10.1001/jamaoncol.2017.1114
2. https://empendium.com/mcmtextbook/chapter/B31.II.22.2.5.
3. Punnapuzha S, Edemobi PK, Elmoheen A. Febrile Neutropenia. [Updated 2023 Mar 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541102/
4. https://www.dnbpediatrics.com/2022/03/febrile-neutropenia.html#Common_Organism_causing_infection_in_Febrile_neutropenia
5. https://reference.medscape.com/calculator/134/mascc-febrile-neutropenia-risk
6. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18(16):3038-3051. doi:10.1200/JCO.2000.18.16.3038
7. https://www.cancercalc.com/CISNE.php#google_vignette
8. Carmona-Bayonas A, Gomez J, Gonzalez-Billalabeitia E, et al. Prognostic evaluation of febrile neutropenia in apparently stable adult cancer patients. Br J Cancer. 2011;105(5):612-617. doi:10.1038/bjc.2011.284
9. Carmona-Bayonas A, Jimenez-Fonseca P, Virizuela Echaburu J, et al. Prediction of serious complications in patients with seemingly stable febrile neutropenia: validation of the Clinical Index of Stable Febrile Neutropenia in a prospective cohort of patients from the FINITE study. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(5):465-471. doi:10.1200/JCO.2014.57.2347
10. 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. doi:10.1093/cid/cir073
11. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 3.2024. http://www.nccn.org.

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