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 最常见的诊断是中性粒细胞减少症或移植物抗宿主病(GVHD)儿童的肺部。 最初的临床怀疑是肺部IMI(PIMI)，通常基于胸部CT发现的病变，并进行分类 “可能的PIMI”。额外的诊断测试通常仅限于有风险的侵入性检查。 配置文件。本研究的目的是建立一种全面的非侵入性诊断方法。 300名患有长期中性粒细胞减少症或GVHD的儿童的前瞻性多中心队列研究 PIMI。建立准确的非侵入性诊断策略可以减少侵入性疾病的发病率 减少适当的抗真菌治疗的时间，从而降低IMI的死亡率。至 要做到这一点，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个网站，也是唯一一个致力于儿科侵袭性真菌疾病的组织。这项研究将有益于 来自与世界上最大的组织儿童肿瘤学小组(COG)无与伦比的合作 致力于儿童癌症临床试验。在目标1中，我们将研究一种全面的非侵入性诊断 在新确诊的PIMI儿童中确认是否存在已证实或可能的PIMI的测试方法 可能是PIMI。我们假设一种非侵入性的诊断策略使用现有的基于血液的分析 (半乳甘露聚糖、曲霉聚合酶链式反应和毛霉菌聚合酶链式反应)将提供阳性和阴性的测试后概率 在临床上很有价值。在目标2中，我们将利用这一队列来比较儿童与 经验性抗真菌治疗与侵入性诊断程序相比可能发生的PIMI 以结果为基础的管理。比较将使用包含两者的结果分数衡量标准 每次暴露的消极和积极后果，提供了对临床影响的平衡衡量 决定。我们建立了一个最小临床重要差值(MCID)，将结果分为 临床真菌学调查专家的“成功”或“失败”。我们假设接受经验剂的患者 与接受侵入性诊断的患者相比，抗真菌药物将有更成功的结果 程序。这一队列还提供了研究新的非侵入性诊断测试的可能性，这些测试并不是广泛可用的。 因此，在目标3中，我们将在患者的子集中探索宿主对已证实的/可能的PIMI的反应 RNA-Seq用于定义转录特征，并评估无浆细胞DNA/RNA下一代 测序以检测霉菌病原体。在选定的地点，我们还将使用呼气测试来评估挥发性代谢物 签名作为IMI的标记。综上所述，我们将建立一种新的实用全面的无创 在一个独特的多中心前瞻性儿科研究中使用一组分析对可能的PIMI的诊断方法 一群人。我们还将首次比较经验式管理和经验式管理的儿童的结果。 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.