Human epidemiology and response to SARS-CoV-2 (HEROS)

人类流行病学和对 SARS-CoV-2 的反应 (HEROS)

• 批准号: 10230381
• 负责人: James E. Gern
• 金额: $ 40.31万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-09 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230381
• 关键词: 16 year old; Address; Adolescence; Adolescent; Allergen Immunotherapy; Allergens; Allergic; Anti-Cholinergics; Asthma; Bacteria; Biological; Birth; Body mass index; Caring; Cells; Characteristics; Child; Childhood; Childhood Asthma; Clinical; Cohort Studies; Collaborations; Complex; Development; Dictyoptera; Disease; Disease Progression; Disease remission; Environment; Environmental Exposure; Environmental Risk Factor; Epidemic; Epigenetic Process; Epitopes; Exposure to; Goals; Grant; Guidelines; House Dust; Household; IgE; Immune; Immune response; Immunobiology; Immunologics; Immunotherapy; Incidence; Inflammation; Interleukin-5; Intervention; Lead; Leptin; Life; Link; Mediating; Metabolic; Microbe; Nursery Schools; Obesity; Outcome; Participant; Particulate Matter; Peripheral Blood Eosinophilia; Phenotype; Plasma; Population; Prevalence; Prevention; Process; Protocols documentation; Recurrence; Research Design; Respiratory Tract Infections; Risk; Risk Factors; Role; SARS-CoV-2 infection; Severities; Shapes; Source; Stimulus; Systems Biology; T cell response; T-Lymphocyte; Testing; Wheezing; Work; aged; airborne allergen; airway epithelium; allergic airway disease; asthmatic; asthmatic patient; base; cockroach allergen; cohort; design; disorder control; early childhood; genetic risk factor; gut microbiome; high risk; immunoregulation; improved; in utero; infancy; inner city; mepolizumab; microbial; microbiome; microbiome composition; mouse allergen; omalizumab; prevent; respiratory microbiome; response; subcutaneous; therapy design; urban setting

COVID-19 SURVEILLANCE STUDY SARS-CoV2 causes severe respiratory disease seen predominantly in adults (COVID-19), but there is little information regarding the infection burden in children. This is complicated by the observation that many virologically-confirmed cases in children are asymptomatic. Undocumented, and likely infectious, cases could result in exposure to a far greater proportion of the community than would otherwise occur. Indeed, it has been proposed that undocumented (or silent) infections are the source for almost 80% of documented infections (Li et al, Science); thus, it is critical to determine the silent and symptomatic infection rate in children. To overcome challenges for clinical study implementation imposed by current healthcare access restrictions, we propose a surveillance study to determine the prevalence of SARS-CoV2 infection (detection of virus in nasal secretions) over time in children and their household contacts (caregivers and siblings). In addition to the need for surveying children for asymptomatic SARS-CoV-2 infection, this study will allow a comparison between children with asthma and other atopic conditions and children without those conditions. Figure 3.1 Study Overview Study design We propose to conduct a prospective surveillance study in which children (index child) and their household contacts, including caregiver(s) and siblings, will be enrolled at study sites with NIH-funded studies. Potential participants are those enrolled in existing NIH-funded studies (including the Wisconsin Infant Cohort Study, the Childhood Origins of Asthma [COAST] study, the MUPPITS-2 study, the RACR study and the Urban Environment and Childhood Asthma [URECA] study). The intent is to recruit children who have asthma and/or other atopic conditions, as well as healthy children, with extensive medical information and information on atopic status available as part of their participation in cohort studies. The enrollment goal is approximately 2000 families to be enrolled over approximately 2 weeks, and each participant will be observed for 6 months. During the study, biological samples will be collected by the family at pre-determined intervals and symptom and exposure surveys will be completed on-line at the time the biological samples are collected (Figure 1 Study Overview). Some biological samples (nasal swabs and stool) will be collected by the caregiver at home. Blood samples will be collected at a home study visit or at an independent clinical laboratory, depending on feasibility. Samples will be processed in central laboratories, and Rho Inc. will serve as the coordinating center for the study. The primary outcome of the study will be the percent of index children and their household contacts with detectable SARS-CoV2 in nasal secretions. Secondary and exploratory outcomes are as described in the study protocol. Project Summary (Primary award-ICAC) The overall goals of our proposal are designed to address current high priority unmet needs in asthma that exist in inner cities, as well as elsewhere, including efforts to apply immune-based strategies to reduce severity, diminish progression of disease, and test strategies to prevent asthma. In that context, we hypothesize that environmental exposure to allergens, particularly cockroach, is a major risk factor for allergic sensitization and the development of asthma, and an important determinant of disease progression plus a target for immunotherapy, severity and responsiveness to treatment. Moreover, we hypothesize that IgE-sensitization, IgE-mediated processes, and wheezing with respiratory infections are important and linked risk factors in the development of asthma, and by targeting treatment to regulate IgE early in life it may be possible to prevent the progression from recurrent wheezing to asthma. Furthermore, asthma in inner-city children is represented by multiple phenotypes, some of which have uncontrolled disease which will benefit by treatment directed towards phenotypic characteristics of their disease, e.g. exacerbation prone and obesity. Listed below are our proposals to reach our goals and reduce unmet needs of asthma in the inner city. 1. Aim 1. URECA, Urban Environment and Childhood Asthma is our inner-city birth cohort that was designed to establish the role and contribution of environmental risk factors on immune development and function that lead to asthma which will be further accomplished by studying the children until they are 14 to 16 years of age, and by this approach determine asthma phenotypes and progression of disease. 2. Aim 2. The Influence of the Inner City House Dust Microbiome and Respiratory and Gastrointestinal Microbiome Composition Function and their Relationships to Allergic Outcomes. The overall aim of this mechanistic study is to determine whether the household environment represents a significant source of bacteria that (1) populates respiratory and/or gastrointestinal microbiomes in early infancy; (2) to identify the key microbial species and function in both of these host niches that are associated with protection from asthma; (3) to identify the microbial metabolic products and their function to shape immune responses; and (4) to pursue the development of protective microbes as a treatment intervention to prevent asthma. 3. Aim 3. Systems Biology Analysis in URECA. The overall aim of this mechanistic study is to extend the current ICAC2 epigenetic study to the application of a systems biology analysis to more fully establish the complex integration of in utero and post-natal environmental stimuli, inherited factors, and dynamic biological responses in early childhood that predispose children in the inner city towards a Th2 phenotype and place them at risk for the development of asthma. 4. Aim 4. The Immunobiology of Cockroach Sensitization – The Role of T Cells in Disease and Immunotherapy is a mechanistic study designed to test the hypothesis that different T-cell responses to epitopes from aeroallergens, in this case cockroach, are important in the development of allergic airway disease and to determine their roles in immunomodulation by immunotherapy. The proposed work will involve extensive collaboration with Aims 1 and 6. 5. Aim 5. Preventing Progression to Asthma in Pre-School Aged Inner City Children (PAPI). This protocol is aimed at the prevention of progression from recurrent wheezing to asthma and will address the hypothesis that treatment of high-risk inner-city children with allergic sensitization and recurrent wheeze with omalizumab, an intervention directed towards IgE, will alter disease progression as reflected by a reduced prevalence of asthma 2 years after the completion of omalizumab therapy. 6. Aim 6. Cockroach (CR) Immunotherapy (IT) in Inner-City Asthma: Effects on Disease Activity and Progression. The primary objective of this protocol is to determine whether the addition of cockroach (CR) subcutaneous immunotherapy (IT) to standard, guideline-directed asthma management is superior to standard asthma care alone in the treatment of persistent asthma in young inner-city children. Furthermore, by focusing on younger children, we will also test a key secondary hypothesis as to whether the addition of CR IT will lead to a long-term reduction in asthma severity and persistence. 7. Aim 7. Asthma Phenotype Informed Protocol (APIP). This protocol is designed to determine if the addition of mepolizumab, anti-IL-5, to treatment of children with difficult-to-control asthma and peripheral blood eosinophilia (>300 cells/mm3) will prevent exacerbations, improve disease control, and potentially prevent progression of disease. 8. Aim 8. The Use of Long-acting Anti-Muscarinic Antagonist (LAMA) Therapy in an Asthma and Obesity Phenotype in Inner-City Asthma. This protocol is designed to test the hypothesis that asthmatic children/adolescents with a BMI >85th percentile have enhanced parasympathetic airway tone, which is related to higher plasma leptin concentration and, as a consequence, will have a greater response to anticholinergic treatment than asthma patients with lower BMIs.

COVID-19-19.监视研究 SARS-COV2引起严重的呼吸道疾病，主要是成年人（Covid-19），但几乎没有 有关儿童感染的信息。观察到许多 儿童病毒学确认的病例无症状。无证件，可能是感染力的案件 导致与社区相比，社区的比例要比以其他方式更大。确实，已经 提出，无证件（或沉默）感染是近80％的记录感染的来源（李 等，科学）；因此，确定儿童的沉默和症状感染率至关重要。 为了克服当前医疗保健访问限制施加的临床研究实施的挑战， 我们提出了一项监视研究，以确定SARS-COV2感染的患病率（检测病毒中的病毒 鼻分泌物）随着时间的流逝，儿童及其家庭接触（护理人员和兄弟姐妹）。除了 需要对儿童进行无症状SARS-COV-2感染的需求，这项研究将允许比较 在患有哮喘和其他特应性疾病的儿童与没有这些条件的儿童之间。 图3.1研究概述 研究设计 我们建议进行一项前瞻性监视研究，其中儿童（索引儿童）及其家庭 包括护理人员和兄弟姐妹在内的联系人将在NIH资助研究的研究地点招募。潜在的 参与者是参加现有NIH资助研究的参与者（包括威斯康星州婴儿队列研究， 哮喘[海岸]研究，Muppits-2研究，RACR研究和城市的童年起源 环境和童年哮喘 [reca]研究）。目的是招募患有哮喘和/或其他特应性疾病的儿童以及 健康的孩子，拥有广泛的医疗信息和有关特定状态的信息 参与队列研究。入学目标大约有2000个家庭要注册 大约2周，将观察到每次参与6个月。在研究期间，生物学 家庭将以预定的时间间隔收集样本，症状和暴露调查将是 在收集生物样品时在线完成（图1研究概述）。一些生物学 护理人员将在家里收集样品（鼻拭子和凳子）。血样将在 根据可行性，家庭学习访问或独立的临床实验室。样品将被处理 在中央实验室，Rho Inc.将作为研究协调中心。 该研究的主要结果将是指数儿童及其家庭联系的百分比 鼻分泌物中可检测的SARS-COV2。次要和探索结果如前所述 研究方案。 项目摘要（主要奖-ICAC） 我们提案的总体目标旨在解决当前的高优先级未定的问题 内城和其他地方存在的哮喘需求，包括努力应用 基于免疫的策略，以减少严重程度，减少疾病进展和测试 预防哮喘的策略。在这种情况下，我们假设环境暴露于 过敏原，尤其是蟑螂，是过敏敏感性的主要危险因素， 哮喘的发展，以及疾病进展的重要决定因素以及目标 免疫疗法，严重程度和对治疗的反应。而且，我们假设 IgE敏感性，IgE介导的过程和呼吸道感染的喘息 哮喘发展中的重要且相关的风险因素，并通过将治疗定位为 在生命的早期调节IgE，可能有可能防止进展 哮喘。此外，市中心儿童的哮喘由多种表型表示， 其中一些患有不受控制的疾病，这将受益于针对的治疗 其疾病的表型特征，例如恶化和肥胖。下面列出 是我们实现目标并减少内城哮喘需求未满足的建议。 1。目标1。乌雷卡，城市环境和童年哮喘是我们的内城出生队列 旨在确定环境风险因素对免疫的作用和贡献 导致哮喘的发展和功能将通过研究进一步实现 孩子们直到14至16岁，并通过这种方法确定哮喘 表型和疾病进展。 2。目标2。内城房屋尘埃微生物组和呼吸道的影响 胃肠道微生物组成分及其与过敏性的关系 结果。这项机械研究的总体目的是确定家庭是否是否 环境代表了（1）呼吸道和/或的重要细菌来源 婴儿早期胃肠道微生物组； （2）确定关键的微生物物种和 在这两个与哮喘的保护相关的宿主壁细分市场中的功能； （3）到 确定微生物代谢产物及其塑造免疫反应的功能； （4） 构成受保护的发展 微生物作为治疗干预措施以预防哮喘。 3。目标3。尿素中的系统生物学分析。这项机械研究的总体目的是 将当前的ICAC2表观遗传学研究扩展到系统生物学分析的应用 更充分地建立子宫内和产后环境刺激的复杂整合， 遗传因素和动态生物学反应在幼儿期，使儿童容易患 在内城，朝着TH2表型迈进，并将其危害哮喘的发展风险。 4。目标4。蟑螂致敏的免疫生物学 - T细胞在疾病和 免疫疗法是一项机械研究，旨在检验不同的T细胞的假设 对蟑螂的蟑螂对来自航空果蛋白的表位的反应很重要 发育过敏性气道疾病，并确定其在免疫调节中的作用 免疫疗法。拟议的工作将涉及与目标1和6的广泛合作。 5。目标5。防止学前年龄的内城儿童（PAPI）的哮喘进展。这 协议的目的是预防从复发式旋转到哮喘的进展，并将 解决以下假设：高危高危内城儿童具有过敏敏感性 与omalizumab的经常性旋转（针对IgE的干预措施）将改变疾病 完成后2年的哮喘患病率降低，进展反映了 omalizumab疗法。 6。目标6。城市哮喘中的蟑螂（CR）免疫疗法（IT）：对疾病活动的影响 和进展。该协议的主要目的是确定是否添加 蟑螂（CR）皮下免疫疗法（IT）标准指导的哮喘 在治疗持续性哮喘中，管理仅优于标准哮喘护理 年轻的市中心儿童。此外，通过关注幼儿，我们还将测试一个钥匙 次要假设是添加CR是否会导致长期降低 哮喘的严重性和持久性。 7。目标7。哮喘表型知情方案（APIP）。该协议旨在确定是否 甲珠单抗抗IL-5的添加用于治疗难以控制哮喘的儿童 和外周血嗜酸性粒细胞（> 300个细胞/mm3）将防止恶化，改善疾病 控制，并有可能预防疾病的进展。 8。目标8。在哮喘和 城市哮喘中的肥胖表型。该协议旨在检验以下假设 BMI> 85％的哮喘儿童/青少年增强了副交感神经 气道音调与较高的血浆瘦素浓度有关，结果将 比BMI较低的哮喘患者对抗胆碱能治疗的反应更大。

项目成果

Microbiota epitope similarity either dampens or enhances the immunogenicity of disease-associated antigenic epitopes.

微生物表位相似性会减弱或增强疾病相关抗原表位的免疫原性。

• DOI: 10.1371/journal.pone.0196551
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: CarrascoPro,Sebastian;LindestamArlehamn,CeciliaS;Dhanda,SandeepK;Carpenter,Chelsea;Lindvall,Mikaela;Faruqi,AliA;Santee,ClarkA;Renz,Harald;Sidney,John;Peters,Bjoern;Sette,Alessandro
• 通讯作者: Sette,Alessandro

Wisconsin Upper Respiratory Symptom Survey for Kids: Validation of an Illness-specific Quality of Life Instrument.

• DOI: 10.1038/s41390-021-01395-9
• 发表时间: 2021-12
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Schmit KM;Brown R;Hayer S;Checovich MM;Gern JE;Wald ER;Barrett B
• 通讯作者: Barrett B

It's a lot of work to be nonallergic.

• DOI: 10.1016/j.jaci.2016.11.018
• 发表时间: 2017-03
• 期刊: The Journal of allergy and clinical immunology
• 作者: Sette A;Schulten V
• 通讯作者: Schulten V

Expression of corticosteroid-regulated genes by PBMCs in children with asthma.

• DOI: 10.1016/j.jaci.2018.06.043
• 发表时间: 2019-03
• 期刊: The Journal of allergy and clinical immunology
• 作者: Goleva E;Babineau DC;Gill MA;Jackson LP;Shao B;Hu Z;Liu AH;Visness CM;Sorkness CA;Leung DYM;Togias A;Busse WW
• 通讯作者: Busse WW