Invasive aspergillosis complicating severe influenza

项目摘要 烟曲霉和其他曲霉菌的侵袭性感染是导致死亡和 在严重免疫抑制的宿主中的发病率。最近，侵袭性曲霉病被描述为 严重流感感染的并发症，主要发生在没有传统曲霉病风险的患者中 各种因素。尽管流感相关曲霉病(IAA)的病例报告越来越多，但发病率 这种疾病在美国的临床特征尚不清楚。鉴于曲霉病的危险因素 在免疫抑制人群中被很好地描述，它们还没有被定义为重症患者 流行性感冒。在迄今为止规模最大的IAA研究中，研究人员对该病的回顾性诊断为14%-19%。 2009-16年欧洲7家医院重症监护病房(ICU)流感患者的死亡率； IAA为50%。在单个ICU的回顾报告中已经描述了类似的发病率，但 在大多数严重流感的多中心研究中，曲霉重叠感染的比例较低。在没有的情况下 对严重流感患者的曲霉病进行系统检测，可能IAA低于- 得到了美国临床医生的认可，但在文献中报道不足。与此同时，发病率可能被夸大了。 在自由接受血清或支气管肺泡灌洗液(BALF)的欧洲回溯性研究中 半乳甘露聚糖作为疾病的明确标志。我们在这个项目中的目标是定义发病率、临床 通过在美国对IAA进行第一次前瞻性研究，了解IAA的特征和风险因素。我们会 采用严格的IAA病例定义和系统的血清和BALF半乳甘露聚糖诊断检测ICU 患有严重流感的患者。我们假设我们将展示美国的IAA比率为 与欧洲报道的结果相当，并且一种新的护理点半乳甘露聚糖侧向流动分析(LFA) 对IAA的诊断具有很强的敏感性和特异性。在目标1中，我们将进行前瞻性的， 美国不同地区4个大型医疗中心ICU中IAA的临床观察性研究。在目标2中， 我们将评估血清和BALF半乳甘露聚糖LFA诊断IAA的性能。我们的发现将 使我们能够制定策略，快速准确地识别IAA患者。这项研究致力于 对一种未得到充分认识的形式的传染病的流行病学和临床方面的理解存在根本差距 侵袭性曲霉病。它将导致临床试验，在这些试验中，对IAA及其诊断的更好的理解是 用于指导早期抗真菌治疗策略，以及未来IAA发病机制的实验室研究。 该项目是可行的，因为我们由杰出的医生组成的协作团队拥有多学科的专业知识- 调查人员。最后，这项研究得到了美国疾病控制和预防中心和一个 最近成立的国际IAA联盟，将有助于设计和执行后续行动的关系 项目。

Project Summary Invasive infections by Aspergillus fumigatus and other Aspergillus species are leading causes of mortality and morbidity among profoundly immunosuppressed hosts. Recently, invasive aspergillosis has been described as a complication of severe influenza infection, predominantly among patients who lack traditional aspergillosis risk factors. Despite an increasing number of case reports of influenza-associated aspergillosis (IAA), the incidence and clinical features of the disease in the United States (US) are unknown. Whereas risk factors for aspergillosis are well described in immunosuppressed populations, they have not been defined for patients with severe influenza. In the largest studies of IAA to date, investigators retrospectively diagnosed the disease in 14%-19% of intensive care unit (ICU) patients with influenza at 7 European hospitals from 2009-16; the mortality rate of IAA was 50%. Comparable incidence has been described in retrospective reports from single ICUs, but rates of Aspergillus superinfections in most multi-center studies of severe influenza have been lower. In the absence of systematic testing for aspergillosis among patients with severe influenza, it is possible that IAA is under- recognized by US clinicians and under-reported in the literature. At the same time, incidence may be overstated in the retrospective European studies by liberal acceptance of serum or bronchoalveolar lavage fluid (BALf) galactomannan as definitive markers of disease. Our objectives in this project are to define the incidence, clinical characteristics, and risk factors of IAA by conducting the first prospective study of the disease in the US. We will employ strict IAA case definitions and systematic serum and BALf galactomannan diagnostic testing of ICU patients with severe influenza. We hypothesize that we will demonstrate rates of IAA in the US that are comparable to those reported in Europe, and that a novel point-of-care galactomannan lateral flow assay (LFA) will demonstrate strong sensitivity and specificity for diagnosing IAA. In aim 1, we will conduct a prospective, observational clinical study of IAA in ICUs at 4 large medical centers from different regions of the US. In aim 2, we will evaluate the performance of serum and BALf galactomannan LFA for diagnosing IAA. Our findings will allow us to develop strategies for rapidly and accurately identifying patients with IAA. This study addresses fundamental gaps in understanding of the epidemiology and clinical aspects of an under-appreciated form of invasive aspergillosis. It will lead to clinical trials in which improved understanding of IAA and its diagnosis are used to guide early antifungal treatment strategies, as well as to future laboratory studies of IAA pathogenesis. The project is feasible due to the multidisciplinary expertise of our collaborative team of pre-eminent physician- investigators. Finally, the study has the support of the US Centers for Disease Control and Prevention and a recently-formed international IAA consortium, relationships that will useful in designing and executing follow-up projects.