Viral persistence & the microbiome in bronchiolitis and risk of recurrent wheeze

病毒持续存在

• 批准号: 9260759
• 负责人: Jonathan M Mansbach
• 金额: $ 70.83万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-14 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260759
• 关键词: 3 year old; 6 year old; Address; African American; Age; Aspirate substance; Asthma; Bacteria; Blood; Bronchiolitis; Child; Childhood; Childhood Asthma; Cohort Studies; Collaborations; Consent; DNA; Data; Development; Diagnosis; Enrollment; Freezing; Funding; Gammaproteobacteria; Grant; Hispanics; Hospitalization; Immune response; Infant; Infection; Intensive Care Units; International; Interview; Knowledge; Lactobacillus; Lead; Lung diseases; Medical Records; Moraxella; Nose; Parents; Participant; Pathogenesis; Pattern; Play; Primary Prevention; Prospective cohort study; Recovery; Recurrence; Research; Research Personnel; Respiratory System; Respiratory syncytial virus; Respiratory tract structure; Rhinovirus; Ribosomal RNA; Risk; Risk Factors; Role; Site; Strategic Planning; Sum; Surveys; Swab; Testing; Time; United States National Institutes of Health; Viral; Virus; Virus Diseases; Wheezing; asthma prevention; clinically relevant; cohort; follow-up; high risk; high risk population; improved; indexing; microbiome; microbiota; multidisciplinary; novel; personalized medicine; prevent; primary outcome; public health relevance; respiratory; treatment strategy; ward

 DESCRIPTION (provided by applicant): Bronchiolitis is the #1 cause of infant hospitalization in the USA. Small cohort studies (n<210) suggest that ~50% of hospitalized infants with bronchiolitis will develop childhood asthma. Unfortunately, it remains unclear which infants will develop asthma and this knowledge gap has hindered primary prevention efforts. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01 AI-87881; Camargo, PI) is a 17-center prospective cohort study that completed enrollment of 926 infants hospitalized with bronchiolitis (85% ward, 15% intensive care unit) in April 2014. At start of the hospitalization, site investigators collected nasopharyngeal aspirates, nasal swabs, and blood, including items needed for the modified asthma predictive index (mAPI) and DNA. We also have extensive interview and medical records data. In an unfunded add-on study, site teams collected a nasal swab at hospitalization, and parents collected nasal swabs 3-weeks after the hospitalization and again over the summer when the child was healthy. There are extensive interview and survey data; and comprehensive medical records. Follow-up data include biannual parent interviews (~90% follow-up to date), and annual review of medical records. For timing reasons, the primary outcome of the 5- year U01 grant is recurrent wheezing by age 3 years. However, all participants were consented for follow-up to age 6 years to permit ascertainment of asthma. This revised R01 application includes preliminary data generated by testing nasal swabs from 102 participants at both hospitalization and 3 weeks later using 16S rRNA and real-time PCR and sequencing of respiratory syncytial virus and rhinovirus. Although these pilot data are underpowered, the statistically non-significant results suggest novel relations between the nasal microbiota, viral persistence, and recurrent wheezing. We found that increasing Gammaproteobacteria (e.g., Moraxella) was associated with an increased (OR 1.8, P=0.18), and increasing Lactobacillales (e.g., Lactobacillus) a decreased (OR 0.27, P=0.22), odds of recurrent wheezing by a median age of 2.2 years. Similarly, we found an increase in Gammaproteobacteria was associated with an increased (OR=1.9, P=0.19) and Lactobacillales with a decreased odds (OR=0.14, P=0.05) of viral persistence. Viral persistence is defined as having the same virus (delayed clearance) or a different virus (sequential infection) 3 weeks after hospitalization. And children with viral persistence had a non-significant increase in the odds of recurrent wheezing by a median age of 2.2 years (OR 1.8, P=0.21). Using the summer nasal swabs, we also examine if the dysbiosis present at hospitalization persists several months later. The R01 would provide funds to test the almost 2,000 nasal swabs from the entire MARC-35 cohort. We have >80% power in all Aims. The investigators are NIH-funded researchers with expertise in their fields. The study advances the primary prevention of asthma, and matches well with the 2009 NIH strategic plan for pediatric respiratory research.

 描述（由申请人提供）：细支气管炎是美国婴儿住院的第一大原因。小规模队列研究 (n<210) 表明，约 50% 的患有细支气管炎的住院婴儿会发展为儿童哮喘。不幸的是，目前尚不清楚哪些婴儿会患上哮喘，这种知识差距阻碍了一级预防工作。第 35 次多中心气道研究合作 (MARC-35) 研究（U01 AI-87881；卡马戈，PI）是一项 17 中心前瞻性队列研究，于 2014 年 4 月完成了 926 名因细支气管炎住院的婴儿的入组（85% 为病房，15% 为重症监护病房）。 拭子和血液，包括改良哮喘预测指数 (mAPI) 和 DNA 所需的物品。我们还有大量的访谈和医疗记录数据。在一项没有资助的附加研究中，现场团队在住院时收集了鼻拭子，家长在住院后三周以及孩子健康的夏天再次收集了鼻拭子。有丰富的访谈和调查数据；和全面的医疗记录。随访数据包括每半年一次的家长访谈（迄今为止约 90% 的随访）以及医疗记录的年度审查。由于时间原因，5 年期 U01 补助金的主要结果是 3 岁时出现反复喘息。然而，所有参与者均同意随访至 6 岁，以查明哮喘。修订后的 R01 应用程序包括通过使用 16S rRNA 以及呼吸道合胞病毒和鼻病毒的实时 PCR 和测序测试 102 名参与者在住院期间和 3 周后的鼻拭子所产生的初步数据。尽管这些试验数据的说服力不足，但统计上不显着的结果表明鼻腔微生物群、病毒持久性和反复喘息之间存在新的关系。我们发现，随着中位年龄 2.2 岁的增加，伽马变形菌（例如莫拉氏菌）的增加与喘息复发的几率增加（OR 1.8，P=0.18）相关，而乳杆菌（例如乳酸杆菌）的增加与复发性喘息的几率降低（OR 0.27，P=0.22）相关。同样，我们发现γ-变形菌门的增加与病毒持久性的增加（OR=1.9，P=0.19）相关，而乳酸菌的增加与病毒持久性的几率降低（OR=0.14，P=0.05）相关。病毒持续存在定义为住院后 3 周感染相同病毒（延迟清除）或不同病毒（连续感染）。病毒持续存在的儿童复发性喘息的几率中位年龄增加了 2.2 岁（OR 1.8，P=0.21），但没有显着增加。我们还使用夏季鼻拭子检查住院时存在的菌群失调是否在几个月后持续存在。 R01 将提供资金来测试整个 MARC-35 队列中的近 2,000 份鼻拭子。我们在所有目标上都拥有 >80% 的力量。研究人员是美国国立卫生研究院资助的研究人员，在各自领域拥有专业知识。该研究推进了哮喘的一级预防，与 2009 年 NIH 儿科呼吸研究战略计划非常吻合。