Background

In 2017, international guidelines proposed new management of febrile neutropenia in children with cancer, adapted to the risk of severe infection by clinical decision rules (CDRs). Until now, none of the proposed CDRs has performed well enough in high-income countries for use in clinical practice. Our study aimed to build and validate a new CDR (DISCERN-FN) to predict the risk of severe infection in children with febrile neutropenia.

Methods

We did two prospective studies. First, a prospective derivation study included all episodes of febrile neutropenia in children (aged <18 years) with a cancer diagnosis and receiving treatment for it who were admitted for an episode of febrile neutropenia, excluding patients already treated with antibiotics for this episode, febrile neutropenia not induced by chemotherapy, those receiving palliative care, and those with a stem cell allograft for less than 1 year, from April 1, 2007, to Dec 31, 2011 from two paediatric cancer centres in France. We collected the children's medical history, and clinical and laboratory data, and analysed their associations with severe infection. Sipina software was used to derive the CDR as a decision tree. Second, a prospective, national, external validation study was done in 23 centres from Jan 1, 2012, to May 31, 2016. The primary outcome was severe infection, defined by bacteraemia, a positive bacterial culture from a usually sterile site, a local infection with a high potential for extension, or an invasive fungal infection. The CDR was applied a posteriori to all episodes to evaluate its sensitivity, specificity, and negative likelihood ratio.

Findings

The derivation set included 539 febrile neutropenia episodes (270 episodes in patients with blood cancer [median age 7·5 years, IQR 3·7–11·2; 158 (59 %) boys and 112 (41%) girls] and 269 in patients with solid tumours [median age 6·6 years, IQR 2·9–14·2; 140 (52 %) boys and 129 (48%) girls]). Significant variables introduced into the decision tree were cancer type (solid tumour vs blood cancer), age, high-risk chemotherapy, level of fever, C-reactive protein concentration (at 24–48 h after admission), and leucocyte and platelet counts and procalcitonin (at admission and at 24–48 h after admission). For the derivation set, the CDR sensitivity was 98% (95% CI 93–100), its specificity 56% (51–61), and the negative likelihood ratio 0·04 (0·01–0·15). 1806 febrile neutropenia episodes were analysed in the validation set (mean age 8·1 years [SD 4·8], 1014 (56%) boys and 792 (44%) girls), of which 332 (18%, 95% CI 17–20) were linked with severe infection. For the validation set, the CDR had a sensitivity of 95% (95% CI 91–97), a specificity of 38% (36–41), and a negative likelihood ratio of 0·13 (0·08–0·21). Our CDR reduced the risk of severe infection to a post-test probability of 0·8% (95% CI 0·2–2·9) in the derivation set and 2·4% (1·5–3·9) in the validation set. The validation study is registered at ClinicalTrials.gov, NCT03434795.

Interpretation

The use of our CDR substantially reduced the risk of severe infection after testing in both the derivation and validation groups, which suggests that this CDR would improve clinical practice enough to be introduced in appropriate settings.

Funding

Ligue Nationale Contre le Cancer.

中文翻译：

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新临床决策规则 (DISCERN-FN) 的决策树推导和外部验证可预测接受癌症治疗的儿童发热性中性粒细胞减少期间的严重感染风险

背景

2017 年，国际指南提出了癌症儿童发热性中性粒细胞减少症的新管理方法，以适应临床决策规则 (CDR) 的严重感染风险。到目前为止，没有一个提议的 CDR 在高收入国家表现得足够好，可用于临床实践。我们的研究旨在建立和验证一种新的 CDR (DISCERN-FN)，以预测发热性中性粒细胞减少症儿童的严重感染风险。

方法

我们做了两项前瞻性研究。首先，一项前瞻性推导研究包括因发热性中性粒细胞减少症而入院的诊断为癌症并接受治疗的儿童（年龄 <18 岁）的所有发热性中性粒细胞减少症发作，不包括已经接受抗生素治疗的发热性中性粒细胞减少症患者。从 2007 年 4 月 1 日至 2011 年 12 月 31 日，来自法国两个儿科癌症中心的非化疗引起的中性粒细胞减少症、接受姑息治疗的患者以及接受干细胞同种异体移植不到 1 年的患者。我们收集了儿童的病史、临床和实验室数据，并分析了他们与严重感染的关系。Sipina 软件用于将 CDR 导出为决策树。其次，从 2012 年 1 月 1 日起，在 23 个中心进行了一项前瞻性、全国性的外部验证研究，至 2016 年 5 月 31 日。主要结果是严重感染，定义为菌血症、通常无菌部位的细菌培养阳性、具有高扩展可能性的局部感染或侵袭性真菌感染。CDR 应用于所有事件的后验，以评估其敏感性、特异性和负似然比。

发现

推导集包括 539 次发热性中性粒细胞减少症发作（270 次血癌患者发作 [中位年龄 7·5 岁，IQR 3·7-11·2；158 名（59%）男孩和 112 名（41%）女孩）和 269 名实体瘤患者 [中位年龄 6·6 岁，IQR 2·9–14·2；140 (52 %) 名男孩和 129 (48%) 名女孩])。引入决策树的重要变量是癌症类型（实体瘤与血癌）、年龄、高危化疗、发热程度、C反应蛋白浓度（入院后24-48小时）、白细胞和血小板计数和降钙素原（入院时和入院后24-48小时）。对于推导集，CDR 敏感性为 98% (95% CI 93-100)，其特异性为 56% (51-61)，负似然比为 0·04 (0·01-0·15)。在验证集中分析了 1806 次发热性中性粒细胞减少症（平均年龄 8·1 岁 [SD 4·8]，1014 名（56%）男孩和 792 名（44%）女孩），其中 332 名（18%，95% CI 17 –20) 与严重感染有关。对于验证集，CDR 的敏感性为 95% (95% CI 91-97)，特异性为 38% (36-41)，负似然比为 0·13 (0·08-0·21 ）。我们的 CDR 将推导组中严重感染的风险降低到 0·8% (95% CI 0·2-2·9) 和 2·4% (1·5-3·9)验证集。验证研究在 ClinicalTrials.gov 注册，NCT03434795。

解释

在衍生组和验证组进行测试后，使用我们的 CDR 显着降低了严重感染的风险，这表明该 CDR 将改善临床实践，足以在适当的环境中引入。

资金

Ligue Nationale Contre le 癌症。