Mathilde Delebarre

Predicting the risk of severe bacterial infection in children with chemotherapy‐induced febrile neutropenia

The prognosis of febrile neutropenia (FN) in childhood cancer has been considerably improved by the intensification of treatment, including systematic hospitalization and broad‐spectrum antibiotics. As only few children present with a severe bacterial infection (SBI), clinical decision rules have been developed to distinguish those at risk for SBI. The aim of this study was to evaluate the reproducibility of six clinical decision rules proposed in the literature and to compare their performance.

Effect of Nebulized Hypertonic Saline Treatment in Emergency Departments on the Hospitalization Rate for Acute Bronchiolitis: A Randomized Clinical Trial

Importance Acute bronchiolitis is the leading cause of hospitalization among infants. Previous studies, underpowered to examine hospital admission, have found a limited benefit of nebulized hypertonic saline (HS) treatment in the pediatric emergency department (ED). Objective To examine whether HS nebulization treatment would decrease the hospital admission rate among infants with a first episode of acute bronchiolitis. Design, Setting, and Participants The Efficacy of 3% Hypertonic Saline in Acute Viral Bronchiolitis (GUERANDE) study was a multicenter, double-blind randomized clinical trial on 2 parallel groups conducted during 2 bronchiolitis seasons (October through March) from October 15, 2012, through April 15, 2014, at 24 French pediatric EDs. Among the 2445 infants (6 weeks to 12 months of age) assessed for inclusion, 777 with a first episode of acute bronchiolitis with respiratory distress and no chronic medical condition were included. Interventions Two 20-minute nebulization treatments of 4 mL of HS, 3%, or 4 mL of normal saline (NS), 0.9%, given 20 minutes apart. Main Outcomes and Measures Hospital admission rate in the 24 hours after enrollment. Results Of the 777 infants included in the study (median age, 3 months; interquartile range, 2-5 months; 468 [60.2%] male), 385 (49.5%) were randomized to the HS group and 387 (49.8%) to the NS group (5 patients did not receive treatment). By 24 hours, 185 of 385 infants (48.1%) in the HS group were admitted compared with 202 of 387 infants (52.2%) in the NS group. The risk difference for hospitalizations was not significant according to the mixed-effects regression model (adjusted risk difference, –3.2%; 95% CI, –8.7% to 2.2%; P = .25). The mean (SD) Respiratory Distress Assessment Instrument score improvement was greater in the HS group (–3.1 [3.2]) than in the NS group (–2.4 [3.3]) (adjusted difference, –0.7; 95% CI, –1.2 to –0.2; P = .006) and similarly for the Respiratory Assessment Change Score. Mild adverse events, such as worsening of cough, occurred more frequently among children in the HS group (35 of 392 [8.9%]) than among those in the NS group (15 of 384 [3.9%]) (risk difference, 5.0%; 95% CI, 1.6%-8.4%; P = .005), with no serious adverse events. Conclusions and Relevance Nebulized HS treatment did not significantly reduce the rate of hospital admissions among infants with a first episode of acute moderate to severe bronchiolitis who were admitted to the pediatric ED relative to NS, but mild adverse events were more frequent in the HS group. Trial Registration clinicaltrials.gov Identifier: NCT01777347

Which decision rules meet methodological standards in children with febrile neutropenia? Results of a systematic review and analysis

Clinical decision rules (CDRs) have sought to identify the few children with chemotherapy‐induced febrile neutropenia (FN) really at risk of severe infection to reduce the invasive procedures and costs for those at low risk. Several reports have shown that most rules do not perform well enough to be clinically useful. Our objective was to analyze the derivation methods and validation procedures of these CDRs.

Optimization of continuous infusion of piperacillin-tazobactam in children with fever and neutropenia.

The study through Monte Carlo simulation of &bgr;-lactam pharmacokinetic/pharmacodynamic target attainment and determination of subsequent serum concentrations of piperacillin–tazobactam administered through continuous infusion to children treated for fever and neutropenia shows that 400 mg/kg/day has the highest probability of target attainment against Pseudomonas aeurginosa in our oncology ward compared with the standard regimen of 300 mg/kg/day.

Predicting the risk of severe infection in children with chemotherapy-induced febrile neutropenia.

Purpose of reviewChemotherapy-induced febrile neutropenia is a frequent event in children with cancer with possible severe complications. However, increasing evidence indicates that early discharge or outpatient therapy can safely be proposed for children with low-risk febrile neutropenia. Clinical decision rules (CDRs) have been proposed to help predict the risk of severe infection in children with chemotherapy-induced febrile neutropenia, but none has been fully validated. Recent findingsThe aim of CDRs for children with febrile neutropenia would be to identify patients at low risk of severe infection. At least 16 different CDRs have been proposed. Only a few have been tested across multiple datasets. Some CDRs were reproducible, but none fulfilled the requirements for validation. Different definitions of outcome and the lack of rigorous methods for derivation probably explain why no validated CDR yet exists for children with febrile neutropenia. SummaryA consensus definition of the best outcome in clinical practice is essential. It must then be followed by multiple and large-scale validations of a CDR that meets all methodological criteria, with high sensitivity and enough specificity to enable physicians to safely propose an outpatient management strategy for patients identified as at low risk of severe complications related to febrile neutropenia.

Risk-stratification management of febrile neutropenia in pediatric hematology-oncology patients: Results of a French nationwide survey

In 2012, new international guidelines for children with chemotherapy‐induced febrile neutropenia (FN) were issued, recommending reduced‐intensity management strategy based on stratification of infectious risks. Some studies have highlighted practice disparities in different countries and within the same country. Our aim was to assess the current management strategies for the treatment of chemotherapy‐induced FN in children in France.

Which Variables Are Useful for Predicting Severe Infection in Children With Febrile Neutropenia

To distinguish children with chemotherapy-induced febrile neutropenia (FN) at low risk of severe infection, the variables that are significant risk factors must be identified. Our objective was to identify them by applying evidence-based standards. This retrospective 2-center cohort study included all episodes of chemotherapy-induced FN in children in 2005 and 2006. The medical history, clinical, and laboratory data available at admission were collected. Severe infection was defined by bacteremia, a positive culture of a normally sterile body fluid, invasive fungal infection, or localized infection at high risk of extension. Univariate analysis identified potential predictive variables. A generalized mixed model was used to determine the adjusted variables that predict severe infection. We analyzed 372 FN episodes. Severe infections occurred in 16.1% of them. Variables predictive of severe infection at admission were: disease with high risk of prolonged neutropenia (adjusted odds ratio [aOR]=2.5), blood cancer (aOR=1.9), fever ≥38.5°C (aOR=3.7), and C-reactive protein level ≥90 mg/L (aOR=4.5). Now that we have identified these variables significantly associated with the risk of severe infection, they must be validated prospectively before combining the best predictive variables in a decision rule that can be used to distinguish children at low risk.

PS-089 Which Decision Rules Meet Methodological Standards In Children With Febrile Neutropenia? Results Of A Systematic Review And Analysis

Background and aim Clinical decision rules (CDRs) have sought to identify the few children with chemotherapy-induced febrile neutropenia (FN) really at risk of severe infection to reduce the invasive procedures and costs for those at low risk. Several reports have shown that most rules do not perform well enough to be clinically useful. Our objective was to analyse the derivation methods and validation procedures of these CDRs. Methods A systematic review using Medline, Ovid, Refdoc, and the Cochrane Library through December 2012 searched for all CDRs predicting the risk of severe infection and/or complications in children with chemotherapy-induced FN. Their methodological quality was analysed by 17 criteria for deriving and validating a CDR identified in the literature. The criteria published by the Evidence Based Medicine Working Group were applied to the published validations of each CDR to assess their level of evidence. Results The systematic research identified 612 articles and retained 12 that derived CDRs. Overall the CDRs met a median of 65% of the methodological criteria. The criteria met least often were that the rule made clinical sense, or described the course of action, or that the variables and the CDR were reproducible. Only one CDR, developed in South America, met all methodological criteria and provided the highest level of evidence; unfortunately it was not reproducible in Europe. Conclusion Only one CDR developed for children with FN met all methodological standards and reached the highest level of evidence.

SFCE P-06 - Prise en charge des neutropénies fébriles : Enquête nationale Française

Contexte La prise en charge des neutropenies febriles (NF), 2e cause d’hospitalisation en oncohematologie pediatrique a fait l’objet de nouvelles recommandations internationales en 2012 preconisant un allegement therapeutique global base sur la stratification du risque infectieux (regles de decision). Avant ces recommandations plusieurs etudes avaient montree de grandes variations de la prise en charge dans un meme pays. Aucune etude de ce type n’avait ete menee en France. Objectif Connaitre la prise en charge d’un episode de NF dans chaque centre de reference. Methodes Un questionnaire standardise a ete envoye a tous les centres de reference de la societe francaise des cancers de l’enfant. Resultats Tous les centres ont participe avec un taux d’items renseignes de 88%. La definition meme d’un episode de NF etait variable. Il existait 42 combinaisons d’antibiotherapie initiale probabiliste. 17 centres proposaient un allegement therapeutique selon des modalites variables d’un centre a l’autre. Conclusion Il y avait une grande heterogeneite dans la prise en charge des NF en France. Pour appliquer les dernieres recommandations il semble necessaire d’uniformiser les definitions et la stratification du risque infectieux basee sur un outil d’aide a la decision valide.

Still looking for the best variables for decision rules in childhood febrile neutropenia

To the Editor: We thank Baderdeen and St John-Green for their letter, which raised several relevant points. A clinical decision rule (CDR) must have 100% or near-100% sensitivity, because missing a single diagnosis of severe infection in patients with chemotherapy-induced febrile neutropenia (FN)may result in death or at least rapid aggravation of the patient’s condition. It may be safer to delay CDR application for 24–48 hr, thereby limiting invasive treatment and shortening the hospital stay for most patients with low-risk FN. Validation of this CDR in a large population, and impact analysis, is necessary before the rule can be implemented widely in clinical practice. However, effective implementation requires the use of variables that are clearly defined and easy to collect in any facility caring for patients with FN. Although procalcitonin assays tend to be widely available, IL-6 and IL-8 analyses are not. Baderdeen and St John-Green also suggest using the ‘‘presence of a clinical focus of infection’’ as a predictive variable. The use of this variable, when present, might well be interesting, but it must be carefully defined. No CDR is required or even appropriate for patients with a substantial ‘‘clinical focus of infection,’’ such as perineal cellulitis or pneumonia: what they need is careful inpatient surveillance. Additionally, some focal signs are likely to be considered under the outcome definition and others in the definition of the predictive variable ‘‘presence of a clinical focus of infection.’’ Urinary tract infections, for example, as infections in a usually sterile fluid, meet an outcome definition, whereas other focal signs, such as zoster, streptococcal pharyngitis, or skin folliculitis, may be treated as predictive variables. An overlap between the definition of this predictive variable and the outcome should be avoided, for it is a methodological error that may falsely increase the odds ratio observed for this variable and probably invalidate the rule, as it did in the study by Rodinelli et al. [1]. There, the authors considered a systemic inflammatory response syndrome with clinical and laboratory infections in the definition of the outcome, which overlapped with the predictive variable ‘‘clinical focus of infection.’’ This issue of overlap raises the question of the outcome definition. What is the best definition of severe infection? Is it simply bacteremia? Is it significant bacterial infection? Severe infectious complication? Demonstrated invasive bacterial infection? All these terms have been used by others and were mentioned in our article, and their definitions have varied from one author to another [2]. Ammann et al. [3] used the term ‘‘adverse event,’’ summarized as any serious medical complication related to FN, to differentiate between patients at high and low risk of severe infection. This definition, while it may bemore practical or easier to apply, is substantially broader than the risk of infectious diseases in patients with FN. Studies are still needed to validate a CDR for better care of children with chemotherapy-induced FN. A common and useful definition of the outcome must be clearly identified, based on a consensus among pediatricians working on this subject. François Dubos, MD, PhD* Pediatric Emergency and Infectious Diseases Unit EA2694, Public Health Epidemiology and Quality of Care Lille–Nord de France University Hospital CHRU Lille, UDSL