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: 10286384
• 负责人: MICHAEL E PICHICHERO
• 金额: $ 8.97万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286384
• 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.

项目概要/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就诊以及严重的发病率。急性中耳炎（AOM）是一种典型的 病毒-细菌混合感染，机会性鼻咽定植者沿咽鼓管上升至 在并发病毒性上呼吸道感染期间感染中耳。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 发病机制、流行病学和 6 个月至 5 个月的免疫 岁数。容易出现多种 AOM 的儿童，在我们的研究中被称为严格定义的易发性中耳炎 (SOP) 儿童 队列，约占儿童总数的 10%，但占医疗保健的大部分 由于 AOM 造成的负担，并且更有可能接受鼓膜造口管插入手术。很明显，sOP 与非中耳炎倾向 (NOP) 相比，儿童在生命早期就被一种或多种潜在耳病原体定植 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，以便 来确定。初步数据表明，除了鼻咽 (NP) 耳病原体的变化外， 定植和人口危险因素，SOP 儿童在 NP 中具有促炎表型。 岁数。比较 sOP 和 NOP 儿童对 AOM 的 NP 免疫反应的免疫网络模型 表明 IL-6、IL-10、IL-17A 和 CCL5 免疫网络可能是造成免疫差异的原因 在 SOP 儿童中观察到。根据这些数据，我们的假设是，早期生命中耳病原体的定殖改变了 NP 免疫力，从而使一些儿童容易复发 AOM。此外，可溶性NP因子可以是 发现，在生命早期进行测量，将成为复发性 AOM 的预测因子，并为个体化护理提供信息。 目标 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 易感性生物标志物识别之前、期间和之后的指定年龄。目标 2 将测量 从儿童队列的 400 个鼻洗样本中提取 Aim 1 的候选生物标志物，以确定 跨儿童年龄和协变量的生物标志物。因此，本次拨款提案的重点是确定 预测严重复发性 AOM 的生物特征，因此需要插入鼓室造口管 与两岁以下儿童 AOM 感染发生之前或期间测量的观察等待相比 岁数。