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; 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.

项目摘要/摘要 病毒 - 细菌共同感染通常是幼儿中最严重的感染性事件，导致 计划外的办公室和医院就诊以及大量发病率。急性中耳炎（AOM）是一种规范 病毒 - 细菌共感染，机会性鼻咽菌落剂将尤斯塔克式管上升到 在同时病毒上呼吸道感染期间感染中耳。在一项> 1000名儿童的队列研究中 在过去的14年中，我们研究了AOM发病机理，流行病学和免疫力从六个月到五个 年龄。儿童容易发生多个AOM，称为严格定义的中耳炎（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引起的负担，并且更有可能接受鼓膜腔插入的手术。很明显SOP 与易于非目的炎（NOP）相比 儿童，但是这种易感性的预测特征需要在整个早期生活中进行连续监控 确定。初步数据表明，除了发生鼻咽（NP）耳疾病的变化外 殖民化和人口统计风险因素，SOP儿童在NP中具有促炎的表型 年龄。 NP免疫反应与AOM比较SOP和NOP儿童的免疫网络建模 建议IL-6，IL-10，IL-17A和CCL5免疫网络可能导致免疫差异 在SOP儿童中观察到。从这些数据中，我们的假设是，伴随前病原体的早期殖民化改变了 NP的免疫力，因此使一些儿童容易复发AOM。此外，可溶性NP因素可能是 确定，在早期生命中进行衡量，将是复发AOM的预测指标，并为个性化的护理提供了信息。 AIM 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易于识别的AOM敏感性之前，期间和之后定义的年龄。 AIM 2将测量 来自儿童队列的400个鼻洗样品中的AIM 1的候选生物标志物，以确定 儿童年龄和协变量的生物标志物。因此，该赠款提案的重点是确定 对严重复发AOM的生物签名预测，因此需要鼓膜腔插入 在两个以下儿童的AOM感染开始之前或期间将测量的等待与注意力等待 年龄。