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.

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

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

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