Febrile neutropenia remains one of the most critical and common oncological complications, particularly among patients with hematologic malignancies or solid tumors undergoing chemotherapy treatment. In fact, 10–50% of patients with solid tumors and up to 80% of those with hematologic cancers will develop at least one episode of fever associated with neutropenia during chemotherapy [1].

It is clinically defined by an oral temperature exceeding 38.3°C, or two consecutive readings above 38.0°C over a two-hour period, in the presence of an absolute neutrophil count (ANC) below 500/µL, or below 1000/µL with an expected decline to < 500/µL within 48 hours [1, 2].

In neutropenic patients, while progression to sepsis is rapid, classical signs of infection may be absent or attenuated due to the immunosuppressed state. As such, fever often stands as the only clinical manifestation of an underlying infection [3].

The severity of infection is inversely correlated with neutrophil count, with ANC < 100/µL being associated with significantly higher rates of bacteremia and more severe outcomes [2]. Overall, febrile neutropenia carries a substantial burden of morbidity and mortality, with in-hospital mortality rates approaching 10% [2].

To stratify risk and guide management, the Multinational Association for Supportive Care in Cancer (MASCC) risk index is widely used. It takes into account age, clinical presentation, presence of hypotension and hypovolemia, type of primary tumor, comorbidities, and the context of infection (nosocomial versus outpatient). A MASCC score ≥ 21 indicates a low risk of complications with mortality rates under 5%. On the other hand, patients with a MASCC score < 21 should be considered high risk; mortality rates can reach 40% for scores < 15 [4]. Thus, patients with a MASCC score < 21 or with clinical severity criteria should be admitted for inpatient care with immediate initiation of broad-spectrum antibiotic therapy.

Timely administration of antibiotics is a well-established determinant of outcomes in febrile neutropenia. International guidelines from the Infectious Diseases Society of America (IDSA), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) recommend initiating empirical antimicrobial therapy within the first hour following triage and evaluation [1, 3, 4]. Delays in antibiotic initiation have been linked to prolonged hospital stays and increased mortality [5, 6]. A retrospective cohort study including 307 cases of febrile neutropenia showed that each hour of delay in initiating antibiotics increases 28-day mortality by 18% [7].

Despite these recommendations, real-world implementation - particularly in emergency settings - remains inconsistent. The Manchester Triage System (MTS) is a widely used tool in Portuguese EDs to prioritize patient care based on clinical urgency. It assigns patients to one of five categories, each represented by a color code indicating the maximum recommended waiting time for medical assessment: red (immediate assessment), orange (very urgent, within 10 minutes), yellow (urgent, within 60 minutes), green (standard, within 120 minutes), and blue (non-urgent, within 240 minutes) [8]. In many hospitals, these categories are physically signaled by wristbands of corresponding colors, to ensure that healthcare teams can quickly identify priority levels. Although effective for general emergency care, the MTS was not specifically designed for immunocompromised patients, such as those with febrile neutropenia, potentially leading to under-triage and delays in critical treatment. Given the nonspecific or masked clinical presentation of neutropenic patients, combined with the lack of training among triage teams regarding the risks associated with oncological treatments, cancer patients presenting with fever are often assigned a green or yellow triage code and end up being referred to non-specialized teams, leading to significant delays in the initiation of treatment.

To date, no national data have been published evaluating how current triage systems affect time to antibiotic administration in febrile neutropenia cases.

This study aims to evaluate how triage classification of febrile neutropenia patients admitted to the ED influences the time to first antibiotic administration. Furthermore, it seeks to assess the impact of this timing on hospital length of stay and in-hospital mortality.

A retrospective cohort study was conducted including all adult cancer patients admitted to ED of a tertiary hospital - Unidade Local de Saúde Gaia e Espinho, from January to December of 2022, with a final diagnosis of febrile neutropenia. The diagnosis was established according to international guidelines, combining fever (oral temperature > 38.3°C or two consecutive readings > 38.0°C within two hours) with ANC < 500/µL, or < 1000/µL with a projected decrease to < 500/µL within 48 hours.

Clinical and demographic data were retrieved through electronic medical records using the ALERT® and SClínico® systems. Variables collected included triage classification, referral team (Internal Medicine or General Medicine), and time from ED admission to the first administration of antibiotics.

Statistical analysis was performed using IBM SPSS® v27. In the descriptive analysis, continuous variables were presented as mean and standard deviation if normally distributed, and as medians with minimum and maximum values if not normally distributed; categorical variables were presented as absolute frequencies and percentages. Time to initiation of antibiotic therapy was compared between groups defined by triage category and the corresponding referral team, as well as length of hospital stay and in-hospital mortality.

A total of 38 patients with febrile neutropenia were included in the study. The cohort had a male predominance, with 55% male and 45% female patients. The mean age was 68.2 years (standard deviation ± 9.4). In terms of functional status, most patients had preserved autonomy, with 50% (n = 19) classified as ECOG 1, followed by 26,3% (n = 10) ECOG 2, 21.1% (n = 8) ECOG 0, and a single patient (2.6%) with ECOG 3 (Table 1).

Regarding tumor types, 58% (n = 22) had solid tumors, with lung cancer being the most common (21.1%), followed by breast cancer (10.5%). Other primary tumor sites included head and neck, colorectal, pancreas, ovary, leiomyosarcoma, and bladder. The remaining 42% (n = 16) of patients had hematological malignancies, with non-Hodgkin lymphoma (NHL) (23.7%) being the most represented. Other hematological cancers included acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) (Table 1).

Among patients with hematological malignancies, neutropenia was attributed to the disease itself in four patients (two AML, one NHL and one MM with bone marrow infiltration), while the remaining patients were neutropenic as a result of chemotherapy’s hematological toxicity.

The most frequently used chemotherapy regimens among patients with solid tumors were platinum-based doublets (26.3%, n = 10). Among patients with hematologic malignancies, the most common regimen was R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) (18%, n = 7). The interval between the last chemotherapy session and the ED admission was 8.9 days (SD 4.4), which corresponds with the expected nadir period for most cases of chemotherapy-induced neutropenia (Table 1).

Based on the MASCC risk index, 68% of patients (n = 26) had a score ≥ 21, indicating low risk, while 32% (n = 12) were classified as high-risk with scores < 21. All patients presented with ANC < 500 cells/µL at the time of the febrile episode, with half (50%) having severe neutropenia (≤ 100 cells/µL). The most frequent site of infection was the respiratory tract (40%, n = 15), followed by gastrointestinal (18%, n = 7) and genitourinary tract (10%, n = 4). In 32% of patients (n = 12), no infectious focus could be identified (Table 1).

Upon arrival at the ED, the mean time to nurse triage was 7 minutes and 37 seconds (SD 3.77). Fever was the main complaint in over 85% of patients and 68% presented within 24 hours of symptom onset. In 55% of cases, the triage nurse explicitly documented the patient’s ongoing oncological treatment in the notes, indicating general awareness of the relevance of chemotherapy, despite the absence of a standardized mechanism within the triage workflow to flag this clinical context to the ER team.

Patients were assigned different triage codes under the Manchester Triage System (Table 2):

Among yellow coded patients, 19% were high-risk (MASCC < 21), compared to 54% of those with an orange code (Table 2).

Patients triaged to IM had a median time from admission to hemogram result of 1 hour and 30 minutes (IQR 1.46 h), compared to 2 hours and 45 minutes (IQR 3.83 h) for those triaged to GM. The maximum wait times were 6 hours 30 minutes and 8 hours 36 minutes, respectively. There was no statistical significance between both groups (p = 0.46, Mann–Whitney U) (Table 3).

The median time from admission to antibiotic initiation was 4 hours and 27 minutes (min. 1h08, max. 20h32) for patients referred to IM, while it was considerably longer − 7 hours and 46 minutes (min. 3h04, max. 45h20) - for those referred to GM. This difference was statistically significant (p = 0.03, Mann–Whitney U) (Table 3).

A total of 74% (n = 28) of patients required hospitalization, while 26% (n = 10) were managed in the outpatient setting. All 12 patients with a MASCC score of less than 21 were hospitalized. Among those admitted, 64% were hospitalized within the first 24 hours; the remaining 36% were admitted between the second and the fifth day, with delays primarily attributed to the unavailability of inpatient beds.

The most frequently prescribed antibiotic regimen was piperacillin-tazobactam, used in 50% of cases. Other regimens included third-generation cephalosporins with ciprofloxacin (13%), vancomycin (5%) and meropenem (3%); antifungal treatment was given in two patients (5%). Adjustments to the initial antibiotic regimen were required in several cases: 5% and 8% of patients required broadening or narrowing of antibiotic spectrum, respectively, and 8% were switched to targeted therapy after antibiotic susceptibility testing results.

The median duration of hospital stay was 8.5 days (IQR 4.75), with a maximum of 50 days. No statistically significant correlation was observed between the time to antibiotic initiation and the length of hospitalization (p = 0.878, Spearman correlation).

The in-hospital mortality rate was 21% (n = 8). The mean time to death was 4.38 days (SD 3.38), with a maximum of 11 days. Among patients with a MASCC score < 21, the mortality rate was 42%, whereas it was 12% for those with a score ≥ 21. A significant association was found between MASCC score and mortality (p = 0.034, Chi-squared test). No significant association was found between time to antibiotic initiation and mortality (p = 0.82, Mann-Whitney U).

Among the 30 survivors, three were re-admitted due to need for antibiotic adjustment and inpatient care. Six required re-hospitalization, including:

The 30-day mortality rate was 24% (n = 9).

This study highlights important shortcomings in the emergency triage and initial management of patients with febrile neutropenia within a real-world hospital setting. While limited by its small sample size and single-center scope, several key findings merit reflection.

Firstly, the study cohort is likely under-representative of the most severe febrile neutropenia cases. Patients with more advanced clinical deterioration or sepsis may have been coded under alternative diagnoses and thus were excluded from analysis. Additionally, many low-risk patients with solid tumors (particularly those with MASCC scores ≥ 21) were managed at the Oncological Day Hospital and did not require ED evaluation. This department, which operates only during weekday mornings and early afternoon, provides scheduled and unscheduled care including blood draws and intravenous antibiotic administration. In these situations, if there is need for inpatient treatment, the patient is usually directed to the ED along with a letter of referral, which leads to them receiving a white code and to be directed to IM. In our sample, 2 out of 4 patients referred from outpatient clinics lacked formal hemogram results or had pre-initiated antibiotic therapy. A standardized protocol requiring patients to arrive at the ED with a written referral addressed to Internal Medicine and with laboratory testing and antibiotics already initiated could streamline care and reduce avoidable delays. Notably, in our sample, all patients with solid tumors who independently accessed the ED did so during weekends, holidays, or after 2 p.m., periods during which the Day Hospital was unavailable.

It was not possible to know the real time from triage to medical observation, since medical records are often written later. Nonetheless, significant delays were observed in the time from admission to key clinical milestones, reflecting a clear deviation from international recommendations.

Guidelines advocate initiating empirical antibiotic therapy within the first hour of presentation [1, 3, 4]. However, this benchmark was not met in our sample. The median time to antibiotic initiation ranged from 4.5 to nearly 8 hours, depending on triage category and referral pathway. Patients triaged with a yellow code, who accounted for more than half of the sample, experienced the longest delays, particularly when referred to General Medicine. In these patients, time to antibiotic administration was nearly twice as long as in those triaged to Internal Medicine. This discrepancy can be partly explained by systemic organizational factors. Within our institution, the General Medicine team is typically responsible for managing patients triaged as lower-priority (green or yellow codes) and operates under significantly more constrained resources, with a high patient-to-physician ratio and broader clinical responsibilities, which may delay the timely assessment and treatment of high-risk individuals inadvertently triaged to their care.

Although the MASCC score was significantly associated with in-hospital mortality in our sample (p < 0.05), it does not fully account for the elevated mortality rate observed (21%), which is more than double the ~ 10% typically reported in the literature [2]. Notably, even when analysing mortality rates within each MASCC category (scores < 21 and ≥ 21), we found rates higher than those generally expected for both risk groups [4]. One plausible contributing factor to this elevated mortality is triage misclassification. Patients with febrile neutropenia who were not promptly identified as high-risk may have experienced significant delays in diagnostic work-up (e.g., hemogram) and initiation of empirical antibiotic therapy, both of which are time-sensitive interventions. As such, while the MASCC index remains a valuable prognostic tool, its predictive power may be limited in real-world settings where organizational and procedural factors - such as triage delays - play a critical role. On the other hand, contrary to international evidence demonstrating a strong association between delayed antibiotic initiation and adverse outcomes, including increased mortality and longer hospital stays, our analysis did not identify a statistically significant correlation between time to antibiotics and either mortality or length of hospitalization [5–7]. This apparent discrepancy may be explained by several limitations. The relatively small sample size may have reduced the statistical power needed to detect associations. In addition, the study did not control for potentially important confounding variables such as comorbidities (e.g., cardiovascular disease, diabetes), causative pathogens, multidrug resistance, or the presence of bacteremia - all of which could independently influence clinical outcomes.

Future research with larger sample sizes and more comprehensive data collection is warranted to clarify these associations and identify which specific clinical and systemic factors most influence outcomes in this vulnerable population.

This study reveals critical gaps between established guidelines and real-world practice in the management of febrile neutropenia in the ED. The majority of patients failed to receive empirical antibiotic therapy within the recommended first hour after admission, with delays significantly more pronounced in those who received a yellow code and were triaged to General Medicine rather than Internal Medicine. Given the high-risk nature of febrile neutropenia and its associated morbidity and mortality, it is imperative that all oncological patients presenting with fever are systematically referred to Internal Medicine, bypassing generalist pathways that may lead to treatment delays.

These findings support the implementation of a dedicated internal “fast-track” protocol for oncological patients with fever. Such a pathway should include (Fig. 1):

Adopting such a protocol would help ensure timely, guideline-adherent care and may reduce preventable delays, morbidity, and mortality in this vulnerable population. Translating theoretical recommendations into clinical practice is essential to improving outcomes for febrile neutropenia patients. We recommend that this analysis be repeated following the implementation of the fast-track protocol, to assess its impact on key clinical metrics such as time to antibiotic initiation and adherence to international benchmarks, hospitalization duration, and mortality. Ideally, this should be conducted as a multi-center study to enhance the generalizability of findings and support broader implementation across healthcare institutions.

Finally, given the rising incidence of cancer worldwide and projections indicating that it may soon become the leading cause of mortality in developed countries [9], it is crucial to recognize febrile neutropenia as a frequent and potentially life-threatening complication of oncological treatment. Just as dedicated fast-track pathways exist for conditions such as stroke or myocardial infarction, the implementation of an equally robust protocol for febrile neutropenia is imperative to ensure timely, effective care for this growing patient population.

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