Immune biomarker discovery in children susceptible to recurrent otitis media

易患复发性中耳炎的儿童中免疫生物标志物的发现

• 批准号: 10452702
• 负责人: MICHAEL E PICHICHERO
• 金额: $ 8.52万
• 依托单位: ROCHESTER GENERAL HOSPITAL (NY)
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452702
• 关键词: 1 year old; 2 year old; 5 year old; Acute; Address; Age; Age-Months; Applications Grants; Biological Markers; Child; Clinic; Clinical; Cohort Studies; Cytokine Network Pathway; Data; Development; Epidemiology; Eustachian Tube; Event; Frequencies; Goals; Health; Healthcare; Hospitals; Immune; Immune response; Immunity; Immunologic Factors; Immunologic Markers; Immunological Models; Individual; Infection; Inflammatory; Interleukin-10; Interleukin-17; Interleukin-6; Life; Measures; Monitor; Morbidity - disease rate; Nose; Operative Surgical Procedures; Otitis; Otitis Media; Pathogenesis; Patient observation; Pediatric cohort; Phenotype; Population; Predisposition; Proteome; Proteomics; Publishing; RANTES; Recovery; Recurrence; Research; Risk Factors; Sampling; Therapeutic Intervention; Tube; Tympanostomy; Tympanostomy Tube Insertions; Upper Respiratory Infections; Viral; Viral Respiratory Tract Infection; Virus Diseases; Visit; base; biobank; biomarker discovery; biomarker identification; biosignature; candidate marker; care burden; co-infection; cohort; data modeling; improved; middle ear; network models; novel; personalized care; potential biomarker

Project Summary/Abstract Viral-bacterial co-infections are often the most serious infectious events in young children, leading to unplanned office and hospital visits as well as significant morbidity. Acute otitis media (AOM) is a canonical viral-bacterial co-infection, where an opportunistic nasopharyngeal colonizer ascends the Eustachian tube to infect the middle ear during a concurrent viral upper respiratory infection. In a cohort study of >1000 children over the last 14 years, we have studied AOM pathogenesis, epidemiology, and immunity from six months to five years of age. Children prone to multiple AOMs, termed stringently-defined otitis prone (sOP) children in our cohort, comprise approximately 10% of the total child population but account for the majority of the health care burden due to AOM and are more likely to undergo surgery for tympanostomy tube insertion. It is clear that sOP children are colonized early in life with one or more potential otopathogens compared to non-otitis prone (NOP) children, but this predictive feature of susceptibility requires continuous monitoring throughout early life in order to determine. Preliminary data suggests that, in addition to changes in nasopharyngeal (NP) otopathogen colonization and demographic risk factors, sOP children have a pro-inflammatory phenotype in the NP after one year of age. Immune network modeling of the NP immune response to AOM comparing sOP and NOP children suggests an IL-6, IL-10, IL-17A, and CCL5 immune network may be responsible for the immune differences observed in sOP children. From these data, our hypothesis is that early life colonization with otopathogens alters NP immunity, thus leaving some children susceptible to recurrent AOM. Further, soluble NP factors can be identified that, when measured in early life, will be a predictor of recurrent AOM and inform individualized care. Aim 1 will employ LC-MS based proteomics in matched sOP and NOP samples to determine the NP proteome at defined ages before, during, and after AOM susceptibility for biomarker identification. Aim 2 will measure the candidate biomarkers from Aim 1 in 400 nasal wash samples across the child cohort to determine robustness of the biomarkers across child age and covariates. Therefore, this grant proposal focuses on the determination of a bio-signature predictive of severe recurrent AOM and therefore the need for tympanostomy tube insertion versus watchful waiting that will be measured before or during the onset of AOM infections in children under two years of age.

项目总结/摘要 病毒-细菌混合感染通常是幼儿中最严重的感染事件，导致 计划外的办公室和医院访问以及显著的发病率。急性中耳炎（AOM）是典型的 病毒-细菌混合感染，其中机会性鼻咽定殖者沿耳咽管上升， 上呼吸道病毒感染时感染中耳。在一项超过1000名儿童的队列研究中， 在过去的14年里，我们研究了AOM的发病机理、流行病学和从6个月到5个月的免疫力 岁的在我们的研究中，倾向于多发性AOM的儿童被称为严格定义的易发性中耳炎（sOP）儿童。 队列约占儿童总人口的10%，但占医疗保健的大部分 由于AOM的负担，更有可能接受鼓膜造口管插入手术。很明显，sOP 与非耳炎易感性（NOP）相比，儿童在生命早期就被一种或多种潜在的耳病原体定殖 儿童，但这种易感性的预测特征需要在整个生命早期进行持续监测， 来决定。初步数据表明，除了鼻咽（NP）耳病原体的变化外， 定植和人口统计学危险因素，sOP儿童在NP中有一个促炎表型， 年龄。NP免疫应答的免疫网络模型AOM比较sOP和NOP儿童 提示IL-6、IL-10、IL-17 A和CCL 5免疫网络可能是导致免疫差异的原因 在sOP儿童中观察到。从这些数据，我们的假设是，早期生活殖民与耳病原体改变 NP免疫，从而使一些儿童容易复发AOM。此外，可溶性NP因子可以是 在生命早期进行测量时，将是复发性AOM的预测因子，并为个性化护理提供信息。 目的1将在匹配的sOP和NOP样品中采用基于LC-MS的蛋白质组学来确定NP蛋白质组 在AOM易感性之前、期间和之后的规定年龄进行生物标志物鉴定。目标2将测量 在整个儿童队列的400个鼻洗液样本中检测来自目标1的候选生物标志物，以确定 儿童年龄和协变量之间的生物标志物。因此，本补助金建议的重点是确定 生物特征预测严重复发性AOM，因此需要插入鼓膜造口管 与在两岁以下儿童AOM感染发作之前或期间测量的观察等待相比， 岁的