This was a retrospective cohort of pediatric patients treated at INCA, Rio de Janeiro, Brazil, between January 2015 and June 2017.

All patients up to and including 18 years of age who were treated at the emergency department with a diagnosis of febrile neutropenia resulting from chemotherapy for the treatment of solid or hematological cancers who were not previously hospitalized were included, regardless of the stage of the disease. Bone marrow transplant recipients were excluded due to the particularities of this population, such as the immunosuppressive chemotherapy regimen, often associated with irradiation, high frequency of graft-vs.-host disease, infectious complications by bacteria and fungi due to the absence of neutrophils, below normal Tcell quantity and function, persisting for months after transplantation even when the total neutrophil count is already normalized,9 and, finally, the use of the consensus of transplanted patients’, adopted by all studied risk stratification protocols.10 Patients with neutropenia due to causes other than chemotherapy were excluded, as well as unconfirmed fever or lack of medical records.

All patients with febrile neutropenia were admitted and treated with broad-spectrum antibiotic monotherapy, with the initial choice being cefepime or meropenem or piperacillin-tazobactam, according to the colonization, initial diagnostic suspicion, and past pathological history. Data collection covered the exams performed and the patient's clinical evolution from the moment of admission to the end of antibiotic administration, regardless of hospital discharge. Then, each service record was submitted to the classification of the six risk stratification strategies available in the literature, according to their respective protocols.

Care spreadsheets of the pediatric emergency department and the medical records of patients admitted to the pediatric ward were used.

Fever was defined as a single axillary measure, either reported, or at admission, ≥37.8°C. Neutropenia was conceptualized as an absolute neutrophil count ≤500cells/mm3 or between 1000 and 500cells/mm3 with a tendency toward decrease in the next 72h.11 Confirmed microbiological infection was defined as the identification of a pathogen in a sterile site or isolation of a pathogen in a non-sterile site, as long as it was associated with the local symptoms of the affected site. Arterial hypotension was defined as a systolic blood pressure measurement below the 5th percentile for age.4 Hypoxemia was established as oxygen saturation in ambient air <94%.4 Severe mucositis was described as the oropharynx involvement by mucositis that required medication or venous hydration.4 Death was counted as death up to two weeks after admission, with the patient still being treated for a confirmed or suspected infectious process. ICU admission was established for all patients who required vasoactive amines, ventilatory prosthesis, or had imminent risk of death, as declared by the attending physician.

Six validated risk stratification strategies for Pediatrics were applied to all included patients.2–6,8

The primary outcome was the occurrence of microbiological infection. The secondary outcomes were death, ICU admission, and the need for more than two antibiotic agents.

Means, frequencies, odds ratios (ORs), and the respective 95% confidence intervals (95%CIs) were calculated. To assess the performance of each protocol in the risk classification of patients with febrile neutropenia, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated according to the following outcomes: death, ICU admission, microbiological infection, and administration of more than two antibiotic agents. To model the correlation between observations, considering that some patients had more than one episode of febrile neutropenia, the OR and its 95%CI were calculated using the generalized estimation equations (GEE) model with a compound symmetry matrix, having the microbiological infection outcome as a reference. Receiver operator characteristic (ROC) curves were constructed for each outcome according to the risk classification protocols, with the area below the curve being estimated. The analyses were performed using the R program (R Development Core Team [Internet]. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2003. Available from: http://www.R-project.org). The level of statistical significance was set at 5%.

The study was approved by the INCA Research Ethics Committee, CAAE 67238217.2.0000.5274, on 04/31/2017.

A total of 220 episodes of febrile neutropenia were identified and 21 cases were excluded due to suspected, but not confirmed, fever or error in the admission diagnosis record. The 199 episodes included occurred in 118 patients. The mean age was 105.7 months (8.8 years), the median was 90 months (7.5 years), and they ranged from 11 to 222 months. The demographic profile comprised 42.4% Caucasians, 46.6% mixed-race, and 11% Afro-descendant individuals. As for gender, 49.2% were males and 50.8% were females. Regarding the weight assessment of the studied population, the mean body mass index (BMI) was 18.54kg/m2 (8.6–47.48kg/m2).

Seventy-five patients had one episode of febrile neutropenia, 20 patients had two episodes, 15 patients had three episodes, four patients had four episodes, two had five episodes, one had six episodes, and one patient had seven episodes. Thirty patients (15%) used more than two antibiotics during the treatment of febrile neutropenia, eight patients (4%) required admission to the ICU, and only one patient (0.8%) died. The presence of semi- or totally-implanted central venous catheter was verified in 90.7% of patients.

Of the studied cancers, 26.2% were hematological tumors and 73.7% were solid tumors. Table 1 shows the frequency of the types of cancers found.

Microbiological identification was attained in 70 samples, from 45 different episodes of neutropenia, in 27 patients.

The etiological profile of positive samples in patients with febrile neutropenia was as follows: 35 Gram-negative bacteria (50%), 27 Gram-positive bacteria (38.5%), and eight fungi (11.4%). Of this total, 41.4% were isolated from central venous catheters. Among the identified Gram-negative bacteria, the most frequent were Klebsiella pneumoniae (14.2%) and Pseudomonas aeruginosa (14.2%). Of the Gram-positive microorganisms, Staphylococcus sp. (12.8%) was the most common. The occurrence of microbiological infection was not associated with the presence of a central venous catheter (OR 2.78; 95% CI 0.56–13.80), gender (OR 0.77; 95% CI 0.37–1.61), ethnicity/skin color (OR 1.72; 95% CI 0.59–5.03), age (OR 1.00; 95% CI 1.00–1.01), or underlying pathology (OR 1.92; 95% CI 0.44–8.36).

Sensitivity, specificity, PPV, and NPV were calculated for the six protocols. The results are shown in Table 2. The graphical evaluation of the performance of tests for the outcomes of death, ICU admission, microbiological infection, and the need for more than two antibiotics was performed using the ROC curves (Fig. 1).

Figure 1.

Comparative analysis of ROC curves of the protocols used for risk classification in pediatric patients with febrile neutropenia (National Cancer Institute, January 2015–June 2017).

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In the 199 analyzed episodes, the frequency of patients classified as low risk showed differences. Using the Rackoff protocol, 42% of the episodes were considered as low risk, whereas this figure was 55% according to Alexander, 69% according to Rondinelli, 66% according to Santolaya, 39% according to Ammann2003, and finally, 47% according to Ammann2010.

Considering the heterogeneity of the studied population in relation to the age group, underlying pathologies, and chemotherapy protocols, it is possible that the performance of a prospective study carried out over a longer period and with a larger sample might establish better performance indicators in relation to the protocols proposed by the literature. As in any retrospective study, the records of the obtained data were not controlled.17

In conclusion, among the evaluated risk classification strategies, Rackoff showed the best performance in relation to microbiological infection, death, and admission to ICU, making it eligible for prospective evaluation. The practical confirmation of a risk classification strategy should also include factors not covered in this study, such as the social reality of each patient, hospital infrastructure, and the adequacy of an appropriate antibiotic regimen for outpatient follow-up. Regarding the use of a certain strategy and taking into account the institutional differences regarding the definition of the variables used, availability of treatment in the intensive care unit, laboratory resources, promptly performed imaging tests, easy access to the institution, regional, and demographic characteristics, and empirical antibiotic schemes, the authors suggest the necessity of local validation.