Long Term Outcomes and Macrophage Biology in Patients with EVALI

项目摘要 电子烟或电子烟相关肺损伤（EVALI）是一种原因不明的新的严重呼吸道疾病， 治疗和临床结果。尽管在病例识别和早期感染的定性方面取得了进展， 当然，有一些关键问题与EVALI患者的长期后果有关， 导致急性呼吸衰竭的病理机制。Intermountain Healthcare和University of 犹他州从这次疫情爆发的早期阶段就积极参与了EVALI的研究，我们一起 有能力解决这两个重要问题。我们已经建立了一个超过140人的队列 EVALI患者并描述了病例表现和对治疗的反应。我们提供了初始 关于这些个体中肺泡巨噬细胞（AM）的独特外观的信息。我们现在 建议在两种特定的实验中解决关于EVALI的临床和病理生物学问题， 目标。在具体目标1中，我们将利用我们的研究基础设施、短期和长期临床经验， 急性呼吸窘迫综合征（ARDS）的研究作为PETAL网络的一部分， 评估EVALI患者的长期临床结局。我们将使用电子健康记录 评估EVALI前后一年内医疗保健使用和呼吸系统疾病变化的质询 在整个超过140名患者的队列中进行诊断，以及这些患者如何受到合并症的影响。使用 我们将在首次住院后3个月和12个月对80名患者进行评估， EVALI用于确定：（a）EVALI后12个月时呼吸损害的存在和持续性，（B） EVALI后3至12个月内是否出现残留呼吸道症状，（c） EVALI幸存者中的反复vaping，包括设备或墨盒的变化以及 基线精神疾病，（d）复发性vaping与呼吸障碍的相关性，以及（e） EVALI诊断前一年与诊断后一年的医疗保健使用和呼吸系统疾病。 急性疾病的多种特征表明AM炎症反应在 EVALI的发病机制。在特定目标2中，我们将比较10例患者的支气管肺泡灌洗（BAL）样本， EVALI患者与10名“健康”vapers中的患者。使用RNA-seq，我们将识别差异表达的途径。 与没有EVALI证据的vape个人相比，激活EVALI受试者。我们还将使用流 流式细胞术来确定这两组中AM的个体发育和额外的活化特征，并将 在分析来自BAL样品的无细胞上清液中确定肺泡上皮细胞损伤的程度。 这项拟议的工作旨在回答关键的补充问题，以进一步深入了解 EVALI的病理生理学和结局。此外，这项工作的见解将有助于我们不断发展的 了解与vaping相关的风险，为我们未来与电子烟相关的潜在爆发做好准备。 吸烟，并推进我们对急性肺损伤的分子机制的理解。

PROJECT ABSTRACT E-cigarette, or vaping, associated lung injury (EVALI) is a new, serious respiratory disease of uncertain cause, treatment, and clinical outcome. Despite progress in case identification and characterization of the early course, there are key questions related to the longer-term consequences for individuals with EVALI and the pathobiologic mechanisms that lead to acute respiratory failure. Intermountain Healthcare and the University of Utah have been actively engaged in studies of EVALI from the early stages of this outbreak, and together we are well-positioned to address both of these important questions. We have established a cohort of over 140 EVALI patients and have described the case presentation and response to therapy. We have provided initial information concerning the distinct appearance of alveolar macrophages (AM) in these individuals. We now propose to address clinical and pathobiologic questions concerning EVALI in experiments with two Specific Aims. In Specific Aim 1, we will leverage our research infrastructure, experience in short- and long-term clinical studies of acute respiratory distress syndrome (ARDS) as part of the PETAL network, and experience with EVALI to assess the long-term clinical outcomes of patients with EVALI. We will use electronic health record queries to assess changes in healthcare use and respiratory illnesses in the year before vs. after an EVALI diagnosis in the entire cohort of over 140 patients and how those may be influenced by comorbidities. Using validated instrument batteries, we will assess 80 individuals at 3 and 12 months after initial hospitalization for EVALI to determine: (a) the presence and persistence of respiratory impairment at 12 months after EVALI, (b) whether residual respiratory symptoms evolve between 3 and 12 months after EVALI, (c) the distribution of recurrent vaping among EVALI survivors, including changes in devices or cartridges and implications of baseline mental illness, (d) the association of recurrent vaping with respiratory impairment, and (e) changes in healthcare use and respiratory illnesses in the year before vs. after an EVALI diagnosis. Multiple characteristics of the acute illness suggest that AM inflammatory responses play an important role in the pathogenesis of EVALI. In Specific Aim 2, we will compare bronchoalveolar lavage (BAL) samples from 10 patients with EVALI to those in 10 “healthy” vapers. Using RNA-seq we will identify pathways in differentially activated EVALI subjects compared to individuals who vape without evidence of EVALI. We will also use flow cytometry to determine the ontogeny and additional activation features of AM in these two groups, and will determine the extent of alveolar epithelial cell injury in analysis of the cell-free supernatant from BAL samples. This proposed work aims to answer the crucial, complementary questions to shed further insight into the pathophysiology and outcomes of EVALI. Furthermore, insights from this work will add to our evolving understanding of the risks associated with vaping, prepare us for potential future outbreaks associated with e- cigarette use, and advance our understanding of the molecular mechanisms of acute lung injury in general.