Multi-center evaluation of the threat of established and emerging respiratory viral infections in pediatric transplant recipients

对儿科移植受者中已发生和新出现的呼吸道病毒感染威胁的多中心评估

• 批准号: 10367953
• 负责人: JANET A ENGLUND
• 金额: $ 26.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2022-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10367953
• 关键词: 2019-nCoV; Antibody Response; Antiviral Agents; Biological Assay; Biological Markers; Blood; Blood specimen; Bronchiolitis; COVID-19; Child; Childhood; Clinical; Common Cold; Communicable Diseases; Coronavirus; Data; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Outcome; Disease Progression; Early Intervention; Enrollment; Epidemiology; Evaluation; Future; Gene Expression Profile; Genotype; Graft Survival; Guidelines; Health; Hospitalization; Human Metapneumovirus; Immune; Immune response; Immunologics; Infection; Influenza A virus; Learning; Longitudinal Studies; Lower respiratory tract structure; Metagenomics; Morbidity - disease rate; Nose; Nucleic Acids; Organ Transplantation; Otitis Media; Outcome; Participant; Patients; Pneumonia; Prevalence; Research; Respiratory Tract Diseases; Respiratory syncytial virus; Rhinovirus; Risk; Sampling; Sinusitis; Site; Solid; Sore Throat; Source; Specimen; T-Lymphocyte; Testing; Transplant Recipients; Transplantation; Upper respiratory tract; Viral; Viral Load result; Viral Respiratory Tract Infection; Virus; Virus Diseases; adaptive immune response; age group; base; biobank; case control; disorder risk; epidemiology study; evidence base; graft function; hematopoietic cell transplantation; high risk; immunological status; improved; interdisciplinary approach; mortality; novel; nucleic acid detection; optimal treatments; outcome prediction; parainfluenza virus; pathogen; patient population; patient stratification; patient subsets; personalized management; post-transplant; predictive marker; predictive modeling; predictive tools; prospective; respiratory; risk stratification; screening; species difference; tool; treatment strategy; vaccine trial; virology

Respiratory viral infections (RVI) have changed the world. RVI are a leading cause of infectious morbidity and mortality in children undergoing hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT). RVI diagnosis by qualitative PCR screening is sensitive, but unfortunately does not distinguish disease from presence of viral nucleic acid or predict risk for progression from upper to the more severe lower respiratory tract disease (LRTD). In the COVID-19 era, many centers now use pre-transplant RVI screening, but the implications of detection in an asymptomatic host are unknown. Integrating quantitative viral load, viral sequencing, and/or host immune (T cell and antibody) responses could provide novel predictive tools to stratify the risk of developing an RVI and the progression to LRTD. Our objective is to establish a comprehensive RVI diagnostic and disease progression predictive model in children undergoing transplantation. We propose a prospective multi-center epidemiologic study of 2000 pediatric transplant recipients, with a nested case-control immunologic and virologic substudy. This will be the largest study on RVI in any age group of HCT and SOT recipients. We will leverage the Pediatric Transplant ID Network (PIDTRAN), a consortium of 21 nationwide sites and the only group dedicated to pediatric transplant infectious diseases. We will obtain pre-transplant blood and nasal samples in all 2000 transplant participants at enrollment and also blood at day +100 post-transplant. In Aim 1, we will determine the prevalence of viral nucleic assay positivity using qualitative PCR and then perform quantitative PCR (qPCR) and viral sequencing (metagenomics) on positive specimens. We hypothesize that the quantity of respiratory viral nucleic acid or certain viral genotypes will identify patients at risk for RVI or disease progression. In Aim 2, we will develop and validate an immunological classifier to predict risk of RVI and progression to LRTD in a nested substudy focused on three major pediatric viruses: RSV, parainfluenza virus 3, and human metapneumovirus. We will characterize pre-transplant humoral and cellular immune responses in the subset of patients who develop those RVIs compared with pre-transplant immunologic and day +100 post-transplant immune responses from uninfected matched controls. The combination of host response and virologic data (qPCR and viral metagenomics) will also be compared between RVI cases who do or do not progress to LRTD to identify biomarkers. We hypothesize that patients with specific qualitative or quantitative antibody responses and/or specific T cell repertoires to RVI will have superior clinical outcomes. Characterizing a comprehensive viral and host response pre-transplant, we will learn to predict who is at risk of RVI and LRTD and needs early intervention vs. delay of transplant, and when PCR positivity is indicative of potential disease. These results will allow us to generate novel evidence-based pediatric guidelines for personalized clinical management of children undergoing transplant, and also inform future antiviral and vaccine studies in these high-risk patient populations.

呼吸道病毒感染(RVI)改变了世界。RVI是感染性发病率的主要原因， 接受造血细胞移植(HCT)和实体器官移植(SOT)的儿童死亡率。 定性聚合酶链式反应筛查诊断RVI是敏感的，但不幸的是不能区分疾病和 病毒核酸的存在或预测从上呼吸道进展到更严重的下呼吸道的风险 疾病(LRTD)。在新冠肺炎时代，许多中心现在使用移植前RVI筛查，但这意味着 在无症状宿主中的检测结果是未知的。集成定量病毒载量、病毒测序和/或 宿主免疫(T细胞和抗体)反应可以提供新的预测工具来分层发生的风险 RVI和向LRTD的进展。我们的目标是建立一个全面的RVI诊断和疾病 儿童移植过程中的进展预测模型。我们提出了一个前瞻性的多中心 2000例儿科移植受者流行病学研究 分组研究。这将是任何年龄段的HCT和SOT接受者中关于RVI的最大规模的研究。我们将利用 儿科移植ID网络(PIDTRAN)，一个由全国21个站点组成的联盟，也是唯一的组织 致力于儿科移植传染病。我们将在移植前采集血液和鼻腔样本 所有2000名移植参与者在登记时和移植后+100天的血液。在目标1中，我们将 用定性聚合酶链式反应确定病毒核酸检测阳性的流行率，然后进行定量 对阳性标本进行聚合酶链式反应(QPCR)和病毒测序(元基因组学)。我们假设， 呼吸道病毒核酸或某些病毒基因型将识别有RVI或疾病进展风险的患者。 在目标2中，我们将开发和验证一种免疫分类器来预测RVI和进展为LRTD的风险 在一项针对三种主要儿科病毒的嵌套子研究中：RSV、副流感病毒3和人类 偏肺炎病毒。我们将表征移植前体液和细胞免疫反应的亚群 与移植前免疫学和移植后+100天相比，发生RVI的患者 来自未感染的配对对照的免疫反应。宿主反应和病毒学数据的结合 (qPCR和病毒元基因组学)也将在进展为LRTD和不进展为LRTD的RVI病例之间进行比较 以确定生物标记物。我们假设有特异性定性或定量抗体反应的患者 和/或RVI的特异性T细胞谱系将有更好的临床结果。描述全面的 病毒和宿主反应移植前，我们将学会预测谁有RVI和LRTD的风险，并及早需要 干预与移植延迟，以及当PCR阳性预示潜在疾病时。这些结果将 使我们能够为儿童的个性化临床管理生成新的基于证据的儿科指南 进行移植，并为未来在这些高危患者群体中进行抗病毒和疫苗研究提供信息。