Non-Invasive Diagnosis of Pediatric Pulmonary Invasive Mold Infections

侵袭性霉菌感染（IMI）是免疫功能低下患者死亡的主要感染原因。IMI 最常在患有中性粒细胞减少症或移植物抗宿主病（GVHD）的儿童的肺部诊断。 肺部IMI（PIMI）的最初临床怀疑通常基于胸部CT识别的病变， “可能的PIMI”额外的诊断测试通常仅限于有相关风险的侵入性程序 数据区.本研究的目的是建立一个全面的非侵入性诊断方法， 前瞻性多中心队列研究，300例长期中性粒细胞减少或GVHD儿童， 皮米建立一个准确的非侵入性诊断策略可以减少发病率从侵入性 手术和减少适当的抗真菌治疗的时间，从而降低IMI死亡率。到 为了实现这一目标，我们将利用国际儿科真菌网络，一个独特的多学科小组， 全球55个研究中心，也是唯一一个致力于儿科侵袭性真菌病的研究小组。这项研究将有利于 通过与世界上最大的组织儿童肿瘤学组织（COG）的无与伦比的合作， 致力于儿科癌症临床试验。在目标1中，我们将研究一种全面的非侵入性诊断方法， 测试方法，以确认是否存在已证实或可能的PIMI在儿童新发现的 可能是PIMI我们假设使用现有的基于血液的检测的非侵入性诊断策略 （半乳甘露聚糖、曲霉PCR和毛霉目PCR）将提供阳性和阴性检测后概率 临床上有用的信息在目标2中，我们将利用这一队列来比较以下儿童的结局： 可能的PIMI通过经验性抗真菌治疗与侵入性诊断程序进行管理， 基于结果的管理。比较将使用一个结局评分指标，该指标包含 每次暴露的消极和积极后果，提供了一个平衡的措施的影响， 决定我们建立了一个最小临床重要差异（MCID），将结果分为 “成功”或“失败”从调查专家在临床真菌学。我们假设接受经验性治疗的患者 与接受侵入性诊断的患者相比， procedure.该队列还提供了研究尚未广泛使用的新型非侵入性诊断测试的可能性。 因此，在目标3中，我们将在一个患者亚组中探索宿主对已证实/可能的PIMI的反应， RNA-Seq用于定义转录特征，并评估下一代血浆无细胞DNA/RNA 测序以检测霉菌病原体。在选定的地点，我们也会使用呼气测试来评估挥发性代谢物， 签名作为IMI的标记。总之，我们将建立一个新的全面的非侵入性的实用程序， 在一项独特的多中心前瞻性儿科研究中，使用一组检测方法诊断可能的PIMI 队列。我们还将首次比较经验管理儿童与经历管理儿童的结果。 侵入性手术这些结果将为新的循证儿科指南提供基础。

Invasive mold infections (IMI) are a leading infectious cause of death in immunocompromised patients. IMI is most frequently diagnosed in the lungs of children with neutropenia or graft versus host disease (GVHD). Initial clinical suspicion for a pulmonary IMI (PIMI) is often based on lesions identified by chest CT, categorized as “possible PIMI”. Additional diagnostic testing is usually limited to invasive procedures with concerning risk profiles. The objective of this study is to establish a comprehensive non-invasive diagnostic approach in a prospective multi-center cohort of 300 children with prolonged neutropenia or GVHD that present with possible PIMI. Establishing an accurate non-invasive diagnostic strategy could reduce morbidity from invasive procedures and reduce time to appropriate antifungal therapy, resulting in a reduction in IMI mortality. To accomplish this, we will leverage the International Pediatric Fungal Network, a unique multidisciplinary group of 55 worldwide sites and the only such group dedicated to pediatric invasive fungal disease. This study will benefit from an unparalleled collaboration with the Children's Oncology Group (COG), the world's largest organization devoted to pediatric cancer clinical trials. In Aim 1, we will investigate a comprehensive non-invasive diagnostic testing approach to confirm the presence or absence of proven or probable PIMI in children with newly identified possible PIMI. We hypothesize that a non-invasive diagnostic strategy using available blood-based assays (galactomannan, Aspergillus PCR, and Mucorales PCR) will provide positive and negative post-test probabilities that are clinically informative. In Aim 2, we will leverage this cohort to compare the outcomes for children with possible PIMI managed with empiric antifungal therapy vs. an invasive diagnostic procedure followed by management based on results. Comparison will be using an outcome score measure that incorporates both negative and positive consequences of each exposure, providing a balanced measure of the impact of a clinical decision. We established a minimum clinically important difference (MCID) to dichotomize outcome into `success' or `failure' from surveying experts in clinical mycology. We hypothesize that patients receiving empiric antifungals will have more successful outcomes compared to patients undergoing an invasive diagnostic procedure. This cohort also offers the possibility to study novel non-invasive diagnostic tests not widely available. Therefore, in Aim 3, in a subset of patients we will explore the host response to proven/probable PIMI using RNA-Seq to define transcriptional signatures, and assess plasma cell-free DNA/RNA next-generation sequencing to detect mold pathogens. At select sites, we will also use breath testing to assess volatile metabolite signatures as a marker for IMI. In summary, we will establish the utility of a new comprehensive non-invasive diagnostic approach for possible PIMI using a panel of assays in a unique multi-center prospective pediatric cohort. We will also compare, for the first time, the outcomes of children managed empirically vs. undergoing invasive procedures. These results will provide the foundation for new evidence-based pediatric guidelines.