(~30 lines) 2 Bronchiolitis is the #1 cause of hospitalization in US infants, with ~130,000 hospitalizations 3 annually. Small cohort studies (n<210) suggest that 40-50% of infants hospitalized with 4 bronchiolitis will subsequently develop asthma. The greatest challenges for developing primary 5 prevention strategies for this large group of children are the very early identification of 6 modifiable risk factors and the heterogeneity of asthma. The 35th Multicenter Airway Research 7 Collaboration (MARC-35) study (U01AI-87881; Camargo, PI) is a 17-center prospective cohort 8 study that completed enrollment of 921 hospitalized infants with bronchiolitis in 2014. In this 9 diverse cohort (53% African-American or Hispanic), investigators have collected biospecimens, 10 including nasal swabs at the index hospitalization (median age 3 months). Follow-up data 11 include biannual parent interviews and medical records to age 5 years, with >90% follow-up to 12 date. This competitive renewal would extend this largest, most comprehensive severe 13 bronchiolitis cohort in the world by conducting an in-person examination at age 6 years to 14 diagnose and phenotype asthma and by examining nasal airway microRNA and NF?B signaling 15 mediators/outcomes, at both the index hospitalization and at age 6 years.
In Aim 1, we will 16 identify nasal airway microRNAs that are prospectively associated with asthma at age 6 years. 17 In Aim 2, we will determine the inter-relations among airway microRNAs and inflammatory 18 response (e.g., NF?B signaling) and their integrated contributions to risk of incident asthma. 19 Pilot data provide compelling support for our hypotheses. Lastly, using a systems biology 20 approach, Aim 3 will define asthma endotypes by integrating clinical phenotype and molecular 21 data (e.g., airway microRNAs and NF?B signaling) at age 6 years. Among these infants with 22 severe bronchiolitis ? a natural experiment ? we will have a unique opportunity to identify airway 23 microRNAs associated with incident asthma during an important period of lung development 24 that would provide a critical window for primary intervention. Furthermore, using innovative 25 approaches, we will not only investigate underlying mechanisms linking bronchiolitis to incident 26 asthma (e.g., enhanced NF?B signaling) but also identify phenotypes/endotypes of asthma that 27 are likely to respond differently to different interventions. The study will provide a strong 28 evidence base for primary prevention through the future development of targeted interventions 29 (e.g., microRNA-targeting therapy). The investigators are NIH-funded researchers with 30 international expertise in the field. The study advances research on the primary prevention of 31 childhood asthma, and matches well with the 2013 NIAID Strategic Plan.

Public Health Relevance

(relevance): 2-3 sentences In an ongoing, multicenter cohort of 921 infants originally hospitalized with bronchiolitis, the investigators will examine the relation of nasal airway microRNAs in early infancy to risk of developing asthma; they also will phenotype/endotype asthma at age 6 years. Identification of asthma risk factors during early infancy will enable prediction of asthma risk during a critical period of lung development and facilitate the development of novel preventive interventions. The project will advance the primary prevention of childhood asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI127507-02
Application #
9393978
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Dong, Gang
Project Start
2016-12-06
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Wu, Vickie; Abo-Sido, Nora; Espinola, Janice A et al. (2017) Predictors of successful telephone follow-up in a multicenter study of infants with severe bronchiolitis. Ann Epidemiol 27:454-458.e1
Hasegawa, Kohei; Linnemann, Rachel W; Mansbach, Jonathan M et al. (2017) Nasal Airway Microbiota Profile and Severe Bronchiolitis in Infants: A Case-control Study. Pediatr Infect Dis J 36:1044-1051
Hasegawa, Kohei; Stewart, Christopher J; Mansbach, Jonathan M et al. (2017) Sphingolipid metabolism potential in fecal microbiome and bronchiolitis in infants: a case-control study. BMC Res Notes 10:325
Stewart, Christopher J; Mansbach, Jonathan M; Wong, Matthew C et al. (2017) Associations of Nasopharyngeal Metabolome and Microbiome with Severity among Infants with Bronchiolitis. A Multiomic Analysis. Am J Respir Crit Care Med 196:882-891
Hasegawa, Kohei; Mansbach, Jonathan M; Ajami, Nadim J et al. (2016) Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis. Eur Respir J 48:1329-1339