Non-Invasive Diagnosis of Pediatric Pulmonary Invasive Mold Infections

小儿肺部侵袭性霉菌感染的无创诊断

• 批准号: 10543223
• 负责人: Brian T Fisher
• 金额: $ 47.27万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-05 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543223
• 关键词: Non; Invasive; Diagnosis; Pediatric; Pulmonary

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.

侵袭性霉菌感染 (IMI) 是导致免疫功能低下患者死亡的主要原因。 最常见于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。 对肺部 IMI (PIMI) 的初步临床怀疑通常基于胸部 CT 发现的病变，分为以下几类： 额外的诊断测试通常仅限于具有相关风险的侵入性操作。 本研究的目的是建立一种全面的非侵入性诊断方法。 前瞻性多中心队列，由 300 名患有长期中性粒细胞减少症或 GVHD 的儿童组成，这些儿童可能患有 PIMI。建立准确的非侵入性诊断策略可以降低侵入性的发病率。 程序并减少适当抗真菌治疗的时间，从而降低 IMI 死亡率。 为了实现这一目标，我们将利用国际儿科真菌网络，这是一个独特的多学科小组 全球 55 个研究中心和唯一致力于儿科侵袭性真菌病研究的小组将受益于这项研究。 来自与世界上最大的组织儿童肿瘤学组织 (COG) 无与伦比的合作 致力于儿童癌症临床试验 在目标 1 中，我们将研究全面的非侵入性诊断。 确认新发现的儿童是否存在已证实或可能的 PIMI 的测试方法 我们勇敢地采用了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）将提供阳性和阴性的检测后概率 在目标 2 中，我们将利用该队列来比较患有以下疾病的儿童的结果。 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 基于结果的管理将使用结合两者的结果评分衡量标准。 每次暴露的负面和正面后果，提供临床影响的平衡衡量 我们建立了最小临床重要差异（MCID）来将结果分为两部分。 临床真菌学调查专家的“成功”或“失败” 我们与接受经验性治疗的患者进行了斗争。 与接受侵入性诊断的患者相比，抗真菌药物将获得更成功的结果 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，在一部分患者中，我们将使用以下方法探索宿主对已证实/可能的 PIMI 的反应： RNA-Seq 定义转录特征并评估下一代血浆游离 DNA/RNA 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。 总而言之，我们将建立一个新的全面的非侵入性的签名作为标记。 在独特的多中心前瞻性儿科中使用一组检测来诊断可能的 PIMI 我们还将首次比较经经验管理的儿童与接受治疗的儿童的结果。 这些结果将为新的循证儿科指南奠定基础。