Non‐neutropenic fever in children with cancer: Management, outcomes and clinical decision rule validation

Abstract

Introduction Fever and infection are an important complication of childhood cancer therapy. Most research and guideline development has focussed on febrile neutropenia, with a paucity directed at non‐neutropenic fever (NNF). We describe the clinical presentation, management and outcomes of NNF in children with cancer, and externally validate the Esbenshade Vanderbilt (EsVan) clinical decision rules (CDR) to predict bacteraemia. Method Using a prospective database, retrospective data were collected on consecutive NNF episodes (fever ≥38.0°C and absolute neutrophil count >1.0 cells/mm3). Sensitivity, specificity and area under the receiver operator characteristic curve (AUC‐ROC) of the CDR were compared to derivation study. Results There were 203 NNF episodes occurring in 125 patients. Severe sepsis was uncommon (n = 2, 1%) and bacteraemia occurred in 10 (4.9%, 95% confidence interval [CI]: 2.7%–8.8%) episodes. A confirmed or presumed bacterial infection requiring antibiotics occurred in 31 (15%) patients. Total 202 (99%) episodes received at least one dose of intravenous broad‐spectrum antibiotic and 141 (70%) episodes were admitted to hospital. Six (3%) episodes required intensive care unit (ICU)‐level care and there were no infection‐related deaths. The EsVan 1 rule had an AUC‐ROC of 0.67, 80% were identified as low risk, and sensitivity and specificity were 50% and 81.5%, respectively, for a risk threshold of 10%. Conclusions Serious infection and adverse outcome are uncommon in children with NNF. Many children did not have a bacterial cause of infection identified, but were still treated with broad‐spectrum antibiotics and admitted to hospital. National clinical practice guidelines should be developed for this important cohort to enable risk stratification and optimise antibiotic management. Further research is required to determine appropriateness of EsVan CDR in our cohort.

Prospective External Validation of the Esbenshade Vanderbilt Models Accurately Predicts Bloodstream Infection Risk in Febrile Non-Neutropenic Children With Cancer

“…Furthermore, the EsVan models are particularly accurate in predicting which patients are at low risk (<10%) of BSI, which across studies account for 74%-88% of the total number of episodes using a threshold of ANC ≥500/µL (87.0% in the current study). 5,6 Similar to the previous retrospective external validation, the models do slightly overpredict the observed risk of BSI. However, this is felt to be ideal as some types of non-BSIs that require antibiotic therapy such as meningitis or pneumonia can have severe symptoms that mimic BSI.…”

“…The risk of infection-related mortality and complications in pediatric patients with non-neutropenic fever is very low. [3][4][5][13][14][15][16][17][18][19][20] The EsVan models have previously been retrospectively externally validated both in the United States and internationally, and EsVan stratified management has been implemented prospectively at one site showing safety and success of using the model to guide antibiotic management. 5,6,9 This study now adds prospective external validation of the models in over 2,500 episodes across 18 international institutions with C-statistics for all versions >0.77, suggesting that this approach may, in combination with clinical judgment, safely guide clinical practice.…”

“…1 At many pediatric oncology sites, patients with non-neutropenic fever without signs of severe sepsis are routinely given empiric antibiotics regardless of risk assessment. [2][3][4][5] The Esbenshade Vanderbilt (EsVan) models use available clinical and laboratory data to accurately predict the risk of bacterial bloodstream infections (BSIs). 2 These models have been retrospectively externally validated.…”

“…2 These models have been retrospectively externally validated. 5,6 Using risk stratification for these patient events may limit unnecessary antibiotic use, reduce antibiotic resistance, lessen the gut microbiome impact, and reduce health care costs. 7,8 The study sought to evaluate the generalizability and assess the safety of implementing EsVan models at 18 international sites (United States [n 5 16], Australia [n 5 1], and Lebanon [n 5 1]).…”

Epidemiology of bloodstream infections and the impact of antimicrobial resistance in pediatric hematopoietic cell transplant

“…described 86 BSI in the post‐engraftment period, but antimicrobial resistance was not distinguishing between pre and post‐engraftment periods 6 . Data on BSIs occurring in non‐neutropenic patients have been also recently reported and showed a lower frequency of this complication (5% of the episodes) with an overall 5% of episodes observed in the post‐engraftment period, with the highest proportion of cases observed post autologous HSCT 39 . Finally, a large study from Zhu and Coworkers 44 stratified episodes by presence or not of neutropenia and showed that the frequency of antibiotic resistance in Enterobacterales was significantly higher in episodes observed during neutropenia, while non‐glucose‐fermenting GN resistance was more frequent during episodes observed in non‐neutropenic patients.…”